RADIATION THERAPY ONCOLOGY GROUP RTOG

Transcription

RADIATION THERAPY ONCOLOGY GROUP
RTOG 0534
A PHASE III TRIAL OF SHORT TERM ANDROGEN DEPRIVATION WITH PELVIC LYMPH
NODE OR PROSTATE BED ONLY RADIOTHERAPY (SPPORT) IN PROSTATE CANCER
PATIENTS WITH A RISING PSA AFTER RADICAL PROSTATECTOMY
Study Chairs (12/10/13)
Principal Investigator/Radiation Oncology
Alan Pollack, MD, PhD
Department of Radiation Oncology
University of Miami Miller School of Medicine
1475 NW 12th Avenue, Suite 1500 (D-31)
Miami, FL 33136
305-243-4916/FAX 305-243-6493
[email protected]
Pathology Co-Chair
Mahul B. Amin, MD
Cedars-Sinai Medical Center
8700 Beverly Blvd., Suite 8728
Los Angeles, CA 90048
310-423-6631/FAX 310-423-0170
[email protected]
Radiation Oncology Co-Chair
Alex Balogh, MD
Tom Baker Cancer Centre
1331 29 St NW
Calgary Alberta
Canada T2N4N2
403-521-3091/FAX 403-283-1651
[email protected]
Neuropsychology Co-Chair
Jeffrey S. Wefel, PhD, ABPP
Section of Neuropsychology
Department of Neuro-Oncology
University of Texas M.D. Anderson Cancer Center
Unit 431 -- P.O. Box 301402
Houston, TX 77230-1402
713-563-0514/FAX: 713-794-4999
[email protected]
Medical Physics Co-Chair
Daniel Low, PhD
Professor and Vice Chair of Medical Physics
UCLA Radiation Oncology
200 Medical Plaza, Suite B265
Los Angeles, CA 90095
310-983-3205 /FAX 310-794-1984
[email protected]
Senior Statistician
Qiang Zhang, PhD
Radiation Therapy Oncology Group/ACR
1818 Market Street, Suite 1600
Philadelphia, PA 19103
215-574-3197/FAX: 215-928-0153
E-mail: [email protected]
Quality of Life/Outcomes Co-Chair
Deborah Watkins-Bruner, RN, PhD, FAAN
Nell Hodgson Woodruff School of Nursing
Emory University
1520 Clifton Road, Room 232
Atlanta, GA 30322
Phone: 404-712-9695/Fax: 404-727-8514
E-mail: [email protected]
CALGB Co-Chair
Joycelyn L. Speight, MD, PhD
UCSF Comprehensive Cancer Center
1600 Divisadero Street H1031, Box 1708
San Francisco, CA 94143
415-353-7175/FAX 415-353-9883
[email protected]
Urology Co-Chair
Leonard G. Gomella, MD
Thomas Jefferson University
1025 Walnut Street, Suite 1102
215-955-1702/FAX 215-923-1884
[email protected]
ECOG Co-Chair
Richard Whittington, MD
Department of Radiation Oncology
University of Pennsylvania
3400 Spruce Street; 2 Donner
215-662-6515/FAX 215-349-5445
[email protected]
Study details continued on next page
RTOG 0534
RTOG 0534 Study details continued
Update
Update
Update
Amendment 4
Amendment 3
Amendment 2
Update
Update
Amendment 1
Update
Activation
Document History
Version/Update Date
April 29, 2014
December 10, 2013
January 17, 2012
November 23, 2011
December 23, 2010
March 24, 2010
October 22, 2009
March 31, 2009
January 8, 2009
February 13, 2008
February 13, 2008
Broadcast Date
April 29, 2014
December 10, 2013
January 17, 2012
January 17, 2012
January 11, 2011
April 20, 2010
October 22, 2009
March 31, 2009
March 31, 2009
February 13, 2008
February 13, 2008
RTOG Headquarters
1-800-227-5463, ext. 4189
This protocol was designed and developed by the Radiation Therapy Oncology
Group (RTOG) of the American College of Radiology (ACR). It is intended to be
used only in conjunction with institution-specific IRB approval for study entry.
No other use or reproduction is authorized by RTOG nor does RTOG assume
any responsibility for unauthorized use of this protocol.
RTOG 0534
CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION (12/10/13)
To submit site registration
For patient enrollments:
Submit study data
documents:
directly to the Lead
Cooperative Group
unless otherwise
specified in the
protocol:
CTSU Regulatory Office
Please refer to Section 5.0 for
RTOG Headquarters
instructions on using the OPEN system.
1818 Market Street, Suite
1600
Phone: 1-866-651-CTSU
Fax: 215-569-0206
Do not submit study data
or forms to CTSU Data
Operations. Do not copy
the CTSU on data
submissions.
The study protocol and all related forms and documents must be downloaded from the protocolspecific Web page of the CTSU Member Web site located at https://www.ctsu.org. Sites must use the
current form version and adhere to the instructions and submission schedule outlined in the protocol.
CTSU sites should follow procedures outlined in the protocol for Site registration, Patient Enrollment,
Adverse Event Reporting, Data Submission (including ancillary studies), and Drug Procurement.
For patient eligibility: Contact the RTOG Research Associate for Protocol, Data Management section
at 215-574-3214.
For treatment-related questions: Correspond by e-mail (preferred) or by phone with the study chair
designated on the protocol cover page.
For questions unrelated to patient eligibility, treatment, or data submission contact the CTSU Help
Desk by phone or e-mail:
CTSU General Information Line – 1-888-823-5923, or [email protected]. All calls and
correspondence will be triaged to the appropriate CTSU representative.
For detailed information on the regulatory and monitoring procedures for CTSU sites please
review the CTSU Regulatory and Monitoring Procedures policy located on the CTSU members’ website
https://www.ctsu.org
The CTSU Web site is located at https://www.ctsu.org
RTOG 0534
INDEX
Schema
Eligibility Checklist
1.0
Introduction
2.0
Objectives
3.0
Patient Selection
4.0
Pretreatment Evaluations/Management
5.0
Registration Procedures
6.0
Radiation Therapy
7.0
Drug Therapy
8.0
Surgery
9.0
Other Therapy
10.0
Tissue/Specimen Submission
11.0
Patient Assessments
12.0
Data Collection
13.0
Statistical Considerations
References
Appendix I
Appendix II
Appendix III
Appendix IV
Appendix V
Appendix VI
- Sample Consent Form
- Study Parameters
- Performance Status Scoring
- Staging System
- Blood and Urine Collection Kits and Instructions
- Neurocognitive Battery: Certification Process and Test Instructions
RTOG 0534
RADIATION THERAPY ONCOLOGY GROUP
RTOG 0534
A Phase III Trial of Short Term Androgen Deprivation with Pelvic Lymph Node or Prostate Bed Only
Radiotherapy (SPPORT) in Prostate Cancer Patients with a Rising PSA After Radical Prostatectomy
SCHEMA (1/8/09) (3/24/10)
S
T
R
A
T
I
F
Y
SV Involvement
1. No
2. Yes
Prostatectomy Gleason Score
1. Gleason ≤ 7
2. Gleason 8-9
Pre-Radiotherapy PSA
1. PSA ≥ 0.1 and ≤ 1.0 ng/mL
2. PSA > 1.0 and < 2.0ng/mL
R
A
N
D
O
M
I
Z
E
Arm 1: PBRT Alone
PBRT 64.8-70.2 Gy
Arm 2: PBRT + NC-STAD
PBRT 64.8-70.2 Gy + NC-STAD for 4-6 months,
beginning 2 months before RT
Arm 3: PLNRT + PBRT + NC-STAD
PLNRT to 45 Gy and PBRT to 64.8-70.2 Gy,
Pathology Stage
1. pT2 and margin negative
NC-STAD for 4-6 months,
2. All others
beginning 2 months before RT
SV = seminal vesicle; RT = radiotherapy; PBRT = prostate bed RT; PLNRT = pelvic lymph node RT;
NC-STAD = neoadjuvant and concurrent short term androgen deprivation
NOTE: It is mandatory the treating physician determine the radiation therapy technique (3D-CRT vs.
IMRT) to be used prior to the site registering the patient. See pre-registration requirements in Section
5.1. See details of radiation therapy and hormone therapy in Sections 6.0 and 7.0.
Patient Population: (See Section 3.0 for Eligibility) (3/31/09) (3/24/10)
Lymph node negative adenocarcinoma of the prostate treated with radical prostatectomy
Post-radical prostatectomy PSA of ≥ 0.1 - < 2.0 ng/mL; pathologic T3N0/Nx disease or pathologic T2N0/Nx
disease, with or without a positive prostatectomy surgical margin; Gleason ≤ 9
Required Sample Size: 1764
RTOG 0534
RTOG Institution #
RTOG 0534
ELIGIBILITY CHECKLIST (11/23/11)
(page 1 of 4)
Case #
(Y)
1. Is there adenocarcinoma of the prostate treated primarily with radical prostatectomy,
pathologically proven to be lymph node negative by pelvic lymphadenectomy (pN0) or
lymph node status pathologically unknown (undissected pelvic lymph nodes [pNx]?
(Y)
2. Is the post-radical prostatectomy entry PSA ≥ 0.1 and < 2.0 ng/mL at least 6 weeks (45
days) after prostatectomy and within 30 days of registration?
(Y)
3. Does the patient meet one of the following pathologic classifications:
T3N0/Nx disease; or
T2N0/Nx disease……….Margin Negative______
Margin Positive______?
(Y)
4. Is the prostatectomy Gleason score 9 or less?
(Y)
5. Is the Zubrod Performance Status 0-1?
(Y)
6. Is the age ≥ 18?
(Y)
7. Was there a digital rectal exam within 8 weeks (60 days) prior to registration?
(Y)
8. Was a history/physical examination done within 8 weeks (60 days) prior to registration?
(N)
9. Are there distant metastases, based upon the following minimum diagnostic work up?
 A CT scan of the pelvis (with contrast if renal function is acceptable; a noncontrast
CT is permitted if the patient is not a candidate for contrast) or MRI of the pelvis
within 120 days prior to registration;
 Bone scan within 120 days prior to registration and plain films and/or MRI if the bone
scan is suspicious
(Y)
10. Is there adequate bone marrow function, within 90 days prior to registration, defined as
follows?
 Platelets ≥ 100,000 cells/mm3 based upon CBC;
 Hemoglobin ≥ 10.0 g/dl based upon CBC
(Y)
11. Is the AST or ALT < 2 x the upper limit of normal within 90 days prior to registration?
(Y)
12. Was serum total testosterone obtained within 90 days prior to registration and ≥40% of
the lower limit of normal of the assay used? Assay Lower Limit _____, Value_____?
(Y)
13. Did the patient sign a study-specific informed consent prior to study entry?
(N/Y)
14. Was there a palpable prostatic fossa abnormality/mass suggestive of recurrence?
(Y)
If yes, was the abnormality/mass shown by biopsy under ultrasound
guidance not to contain cancer?
(N)
15. Does the patient have N1 disease?
(N/Y)
16. Does the patient have pelvic lymph node enlargement ≥ 1.5 cm in greatest dimension by
CT scan or MRI of the pelvis?
(Y)
If yes, was the enlarged lymph node sampled and found to be negative?
(Continued on the next page)
RTOG 0534
RTOG Institution #
RTOG 0534
(page 2 of 4)
Case #
(N)
17. Did the patient receive androgen deprivation therapy that was started prior to
prostatectomy for > 6 months (180 days) duration (Note: The use of finasteride or
dutasteride (±tamsulosin) for longer periods is acceptable prior to prostatectomy)?
(N)
18. Did the patient receive androgen deprivation therapy that was started after prostatectomy
and prior to registration (Note: The use of finasteride or dutasteride (±tamsulosin) is not
acceptable after prostatectomy - must be stopped within 3 months after prostatectomy.
Androgen deprivation therapy must be stopped within 3 months after prostatectomy)?
(N)
19. Did the patient have neoadjuvant chemotherapy before or after prostatectomy?
(N)
20. Did the patient have prior chemotherapy for any other disease site if given within 5 years
prior to registration?
(N)
21. Did the patient have prior cryosurgery or brachytherapy of the prostate?
(N)
22. Did the patient have prior pelvic radiotherapy?
(N)
23. Did the patient have a prior invasive malignancy (except non-melanomatous skin cancer)
or superficial bladder cancer within the past 5 years?
(N)
24. Does the patient have any of the following severe, active comorbidities?
 History of inflammatory bowel disease;
 History of hepatitis B or C;
 Unstable angina and/or congestive heart failure requiring hospitalization within
the last 6 months;
 Transmural myocardial infarction within the last 6 months;
 Acute bacterial or fungal infection requiring intravenous antibiotics at the time of
registration;
 Chronic obstructive pulmonary disease exacerbation or other respiratory illness
requiring hospitalization or precluding study therapy at the time of registration;
 Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects;
 Acquired Immune Deficiency Syndrome (AIDS) based upon current CDC
definition?
(N)
25. Did the patient have any prior allergic reaction to the study drug(s) involved in this
protocol?
The following questions will be asked at Study Registration:
3D-CRT or IMRT CREDENTIALING IS REQUIRED BEFORE REGISTRATION
(N/Y)
Specify use of IMRT
1. Institutional person registering this case
(Y)
2. Has the Eligibility Checklist been completed?
(Y)
3. In the opinion of the investigator, is the patient eligible?
4. Date Informed Consent signed
RTOG 0534
(Continued on next page)
RTOG Institution #
RTOG 0534
(page 3 of 4)
Case #
5. Participant Initials
6. Verifying Physician
7. Patient’s ID Number
8. Date of Birth
9. Race
10. Ethnicity
11. Gender
12. Country of Residence
13. Patient’s Zip Code
14. Method of Payment
15. Any care at VA or military hospital?
16. Calendar Base Date
17. Randomization Date
(Y/N)
18. Have you obtained the patient's consent for his specimens to be used for research to
learn about, prevent or treat cancer?
(Y/N)
19. Have you obtained the patient's consent for his specimens to be used for research to
learn about, prevent or treat cancer?
(Y/N)
20. Did the patient consent to having someone contact them in the future for new
research not included in this consent?
21. Specify SV involvement
22. Specify Prostatectomy Gleason score
23. Specify Pre-radiotherapy PSA
24. Specify Pathology Stage
(Continued on next page)
RTOG 0534
RTOG Institution #
RTOG 0534
Case #
(page 4 of 4)
25. Specify LHRH agonist planned duration
The Eligibility Checklist must be completed in its entirety prior to web registration. The completed, signed, and
dated checklist used at study entry must be retained in the patient’s study file and will be evaluated during an
institutional NCI/RTOG audit.
Completed by
Date
RTOG 0534
1.0
INTRODUCTION
1.1
Rationale for a Salvage Postoperative Radiotherapy (RT) Trial (1/8/09)
As the use of prostatectomy has increased substantially over the last 10 years, so has the
application of post-prostatectomy radiotherapy (RT). RT is the mainstay of salvage treatment for
men with a persistently detectable PSA (PD-PSA) or a delayed rise in PSA (DR-PSA) without
evidence of metastasis.1-13 Because there are no published salvage RT randomized trials, the
rationale for this treatment is derived mostly from small retrospective series. The largest
retrospective analysis was a multi-institutional effort reported by Stephenson et al.13 They
examined predictors of response to salvage RT and found that high Gleason score, high preradiotherapy PSA, negative prostatectomy surgical margins, short PSA doubling time (PSADT),
and seminal vesicle involvement were independently associated with adverse outcome. Similar
factors have been reported in many of the other retrospective series as well.14 Despite gains in
understanding how to select patients for salvage treatment, level I evidence on the outcome of
patients receiving well-delineated treatment (e.g., RT technique and use of androgen deprivation)
is lacking.
Level I evidence supporting the application of RT to patients treated postoperatively has been
reported for adjuvant RT, and the results are encouraging. The findings of a European
Organization for Research and Treatment of Cancer trial (EORTC 22911)15 showed that adjuvant
RT resulted in a significant delay in biochemical and clinical failure. The results from a Southwest
Oncology Group trial, SWOG 8794,16 were similar, as were those from a preliminary report of a
German Cancer Society trial, ARO 96-02,17 reported at the 2005 American Society of Clinical
Oncology meeting. Adjuvant RT is effective at reducing progression.
Although, there are no published phase III clinical trials examining the efficacy of salvage
radiotherapy for a rising PSA after radical prostatectomy, one study has completed accrual.
RTOG 96-01 compares salvage RT alone to salvage RT plus 2 years of androgen deprivation
(AD), accomplished using 150 mg/day of Casodex. The trial described here differs from RTOG
96-01 in several ways. First, the eligibility criteria are stricter; more favorable patients have been
selected for RTOG 0534. Second, short-term AD is being tested, while in RTOG 96-01 long-term
AD was examined. Third, pelvic lymph node radiotherapy was not allowed in RTOG 96-01 and
has never been studied in a randomized trial in post-prostatectomy patients. There is no
consensus on how to apply these treatment methods in the postoperative setting, yet AD and
pelvic lymph node irradiation (PLNRT) are being used.18-26 The proposed three-arm trial is
designed to address the following key questions: 1) Is neoadjuvant and concurrent short-term AD
(NC-STAD) plus prostate bed radiotherapy (PBRT) superior to PBRT alone? and 2) Is NC-STAD
plus pelvic lymph node RT (PLNRT) superior to NC-STAD+PBRT? In the context of this study
description, reference to PLNRT is made with the understanding that the prostate bed will receive
the same total dose in all three treatment arms.
RTOG 0534 is not intended to address the efficacy of RT alone over observation. The complete
response rate (a drop in PSA to undetectable levels) after salvage RT is 70%-80% and durable
responses are observed in 30%-40% of patients. For these reasons, it is likely not feasible or
appropriate to randomize men between observation and salvage RT. The more important issue is
whether the proportion of durable responses is increased by altering the therapeutic approach,
such as the use of NC-STAD with or without extended RT fields.
The pre-salvage radiotherapy PSA doubling time has been reported in several series to be an
important determinant of outcome after radical prostatectomy. Until recently, the consensus was
that men with short PSADTs of ≤6 mo would respond unfavorably to salvage PBRT because of
an increased risk of distant metastasis. Thus, the initial stratification criteria for RTOG protocol
0534 excluded patients with a PSADT of ≤6 mo from eligibility. However, Trock et al,27 in a recent
series from Johns Hopkins reported just the opposite. Those men with a post-prostatectomy
PSADT of ≤6 mo experienced the greatest cause-specific survival benefit from salvage
radiotherapy, when compared to men who did not receive salvage PBRT. There are no other
comparable data available. As a consequence, the eligibility and stratification criteria based on
PSADT have been removed from RTOG 0534. We plan to collect all PSA data so that any
information pertinent to calculating PSADT will be recorded for secondary analyses later.
The eligibility criterion of a PSA ≥0.2 ng/mL has been relaxed to a PSA ≥0.1 ng/mL because
many patients have a documented rise in PSA using hypersensitive assays and are
pathologically high risk by virtue of having pT3 disease and/or a positive margin. These patients
should be treated as early as possible.
1
RTOG 0534
1.2
1.3
Rationale for Using NC-STAD and PLNRT Treatment Postoperatively
No postoperative randomized trials investigating AD plus RT have been published, but three prior
phase III studies of men treated primarily for prostate cancer, one by the RTOG (86-10),28 one by
investigators at Harvard,29 and one by the Trans-Tasman Radiation Oncology Group,30 concluded
that neoadjuvant and concurrent short-term NC-STAD plus RT reduces cause-specific mortality
compared with RT alone. The results of RTOG protocol 94-1331 extend these observations.
RTOG 94-13 compared PLNRT to prostate-only RT and NC-STAD to adjuvant STAD plus RT in
men with newly diagnosed prostate cancer using a 2x2 design. PLNRT significantly delayed
progression, while the timing of STAD did not. When the four treatment groups were examined
individually, the men who received PLNRT plus NC-STAD had significantly fewer failures
(including biochemical) than those in the other three groups. The findings from RTOG 94-13
suggest that there was an interaction between PLNRT and NC-STAD, resulting in a reduction in
progression by more effectively eradicating microscopic pelvic lymph nodal disease. RTOG 0534
builds on the observations of 94-13 and the other randomized trials of men treated primarily with
NC-STAD plus RT in a population of patients who were initially treated with prostatectomy.
RTOG 0534 is a three-arm trial that does not include a PLNRT alone arm. The rationale for a
three-, as opposed to a four-, arm trial is based on two primary considerations. First, a control
arm of PLNRT alone was not included because in RTOG 94-13, it was the NC-STAD plus
PLNRT arm that was superior to all other arms. No difference was seen for PLNRT plus adjuvant
STAD, prostate-only RT plus adjuvant STAD, or NC-STAD plus prostate-only RT, and all were
inferior to NC-STAD plus PLNRT. The hypothesis here is that the combination of NC-STAD plus
PLNRT is necessary to significantly improve outcome when PLNRT is used. Second, a four-arm
study that includes a PLNRT alone arm is prohibitive in terms of patient numbers. As described
below, the three-arm trial design requires 1764 patients, a target that the RTOG is capable of
completing within 9.2 years.
Rationale for Using the PSA Nadir+2 Definition of Biochemical Failure as the Primary
Endpoint
The primary endpoint is freedom from progression (FFP), including a biochemical parameter that
is highly related to clinical progression (CP; includes local, regional, or distant progression). After
radical prostatectomy, a detectable PSA of ≥ 0.2 ng/mL has been associated with a median time
to distant metastasis from prostate cancer of 7-8 years.32-33 There has been debate about the
absolute biochemical cut-point that best correlates with eventual disease relapse (mainly in the
range from 0.1-0.5 ng/mL). In a detailed analysis by Amling, et al34 a biochemical failure cut-point
of 0.4 or greater was found to be more significantly related to eventual CP than lower cut-point
values and was nearly the same as higher cut-point values.
Since the goal here is to use an endpoint that is strongly related to clinical progression and,
ultimately, death due to prostate cancer, we compared a number of PSA-based definitions in a
large cohort of men treated with RT post-prostatectomy.35-36This IRB-approved analysis included
more than 1200 men with lymph node negative disease who were treated with either adjuvant
(23%) or salvage (77%) RT. Median follow-up after RT was 61 months, and there were 147
patients who manifested clinical failure: 13% and 22% at 5 and 10 years, respectively.
Table 1 (below) displays the relationships of different biochemical estimates of CP (BECPs) to
CP for men treated with salvage RT. There are four categories of biochemical parameters
displayed: a) PSA of x ng/mL; b) PSA of x ng/mL plus 2 consecutive rises with the second rise
above the cut-point being tested; c) Three consecutive PSA rises with backdating to between the
nadir and first rise per the ASTRO consensus definition,37 and d) PSA ≥ 2 ng/mL above the nadir
PSA per the “RTOG Phoenix” definition.38-42 The RTOG Phoenix definition was the favored
biochemical failure (BF) definition for men treated primarily for prostate cancer with RT at a
consensus conference organized by the RTOG and ASTRO in January 2005.43 The Phoenix
definition has also been previously referred to as the “Houston” definition40 or simply as nadir +2
ng/mL.38-42 The reports examining the sensitivity, specificity, positive predictive value (PPV), and
accuracy have consistently pointed to the RTOG Phoenix definition as being nearly ideal. Not
only does the RTOG Phoenix definition have high specificity, sensitivity, PPV, and accuracy, the
definition also addresses the pitfalls of the ASTRO definition. The ASTRO definition involves
backdating, which alters the shape of Kaplan-Meier curves (causes an artificial flattening at the
tail end), results in inaccurate estimates of BF when follow-up is short,40,42,44 and overestimates
2
RTOG 0534
BF after release from androgen deprivation.42,44,45 Moreover, during the first two years of follow
up after radiotherapy, the RTOG Phoenix definition identifies patients with BF in greater numbers
than the ASTRO definition, indicating that the classification of BF by the RTOG Phoenix definition
is not delayed in patients treated primarily for prostate cancer.42
Table 1 confirms that the RTOG Phoenix definition is useful for men treated with salvage RT
post-prostatectomy. The highest sensitivity, specificity, and PPVs were obtained for the
definitions that incorporated a 2-ng/mL cut-point. Three definitions were similar: ≥ 2 ng/mL, ≥ 2
ng/mL + two rises, and nadir + 2 ng/mL or higher. Since the RTOG Phoenix definition has
emerged as the BF definition of choice after definitive RT for prostate cancer, and the findings in
Table 1 show that it is likewise a very appropriate BECP definition in the postoperative setting,
the RTOG Phoenix definition will be the primary endpoint in the proposed trial. Biochemical
criteria have previously been included as the primary endpoint in an RTOG randomized trial
examining NC-STAD (RTOG 94-13),31 which supports the rationale for the Phoenix definition as
the primary endpoint in the proposed trial. The initiation of further “salvage” therapy in any form
(e.g., androgen deprivation therapy, vaccine therapy, or chemotherapy) after completion of
protocol treatment and prior to nadir + 2 ng/mL failure will not be counted as a failure and is
strongly discouraged. The success of the trial depends upon allowing the nadir + 2 ng/mL failure
criteria to be met before any other therapeutic intervention. The use of this BECP endpoint
facilitates a trial sample size of 1764 patients (see below), a sample size that is feasible for the
RTOG to accrue in this patient population.
Table 1: Endpoint Considerations from A Pooled Multi-Institutional Analysis
Salvage Only Patients, No AD (n=533)
BECF Definition
1. ≥ 0.2
2. ≥ 0.4
3. ≥ 1.0
4. ≥ 2.0
5. ≥ 0.2+2 rises
6. ≥ 0.4+2 rises
7. ≥ 1.0+2 rises
8. ≥ 2.0+2 rises
9. ASTRO
10. Phoenix
(nadir+2)
%5 / 8 yr.
Failure
59% / 72%
47% / 64%
35% / 52%
29% / 41%
42% / 59%
39% / 57%
32% / 46%
29% / 39%
33% / 36%
31% / 40%
Specificity
Sensitivity
PPV
56%
66%
77%
84%
72%
74%
80%
85%
82%
83%
95%
94%
92%
90%
93%
93%
90%
90%
90%
91%
23%
27%
35%
43%
31%
32%
39%
45%
40%
43%
BECF = biochemical estimate of clinical failure; PPV = positive predictive value
1.4
Other PSA-related measures will be examined as secondary endpoints. A more conventional
early estimate of biochemical failure after radical prostatectomy is a PSA of ≥ 0.4 ng/mL and
rising (two consecutive rises with one being at or above 0.4 ng/mL) at a given time point. A twoyear time point was chosen to reduce the effect of potential delays from short-term AD. In the
analysis shown in Table 1, this endpoint had slightly lower specificity as a BECP. Our plan is to
compare the primary and secondary PSA-related endpoints to the other secondary endpoints of
time to development of hormone refractory disease based on biochemical criteria (three
consecutive rises in PSA modeled after the ASTRO criteria, but without backdating), distant
metastasis, cause-specific mortality, and overall mortality. Local failure is not included as a
separate endpoint because palpable evidence of local recurrence is rare after radiotherapy, and
patients are typically started on salvage AD without prostate bed biopsy. However, local failure
will be recorded and is part of the primary endpoint of biochemical and clinical failure.
Rationale for Biomarker Studies (11/23/11)
The RTOG has been collecting pretreatment diagnostic tissue from all prostate cancer protocols
for over 10 years. A number of histologic, cell kinetic/proliferation, and molecular markers of
apoptosis and angiogenesis are under investigation, with several showing promise for the
stratification of patients in future trials. A focus of prior biomarker studies from the principal
investigators and genitourinary committee has been DNA-ploidy, Ki-67, p53, MDM2, bcl-2, bax,
p16 and Cox-2.46-51 These markers have shown promise in complementing the standard clinical
3
RTOG 0534
parameters of PSA, Gleason score, and stage in prior RTOG (or other) analyses of men with
high-risk features treated primarily with RT, with or without AD. With the exception of DNA-ploidy,
the protein expression of these markers was measured using immunohistochemical methods.
While these markers have been selected based on prior analyses, it is likely that some other
markers and/or methods will be investigated when the proposed trial matures. The quantification
of gene expression based on the RNA level in formalin fixed archival tissue is now possible after
laser capture microdissection and the initial studies on proteomics in archival tissue are
encouraging. Approximately 7 years will be required for this protocol to mature; by that time, a
clearer definition of the markers to be studied will be evident. The plan is to collect and store
tissue from the prostatectomy specimens. The findings are expected to contribute to better risk
group classification, enhance our understanding of radiation response and distant spread, and
lead to therapeutic strategies based on correcting or counterbalancing the abnormalities
detected.
1.5
The collection of blood and urine before and after treatment for proteomic and genomic studies is
also proposed. Preliminary findings of other studies indicate that serum protein patterns defined
through patterns of ion signatures generated from high-dimensional mass spectrometry data may
be of value in determining the presence of prostate cancer.52-53 Likewise, the presence of
prostate cancer has been accurately determined through the identification of hypermethylation of
the glutathione S transferase p1 (GSTP1) gene locus in urine.54 Both of these methods have
potential for predicting outcome in pretreatment samples and the presence of recurrence in
specimens obtained during follow-up. Blood (serum, plasma, and whole blood) and urine will be
collected prior to treatment and during the 6th week of RT. Some blood (serum and plasma) and
urine will continue to be collected at 3, 6, and 12 months in year 1, and then yearly for 6 years
after completion of RT.
Health-Related Quality of Life and Neurocognitive Assessment
Some of the side effects associated with RT and AD are deleterious and affect quality of life, and
others may contribute to increased risks for serious health concerns associated with aging.
Urinary, bowel, and erectile dysfunction are well-known side effects of pelvic RT. Sexual side
effects are the most well recognized adverse effects from AD and include loss of libido, erectile
dysfunction, and hot flashes. Loss of libido is distressing to many men, and they may not pursue
treatments for erectile dysfunction that they may have otherwise pursued after radical
prostatectomy or RT. The incidence of hot flashes, which may not abate over the course of AD, is
close to 80%. Physiologic effects, including gynecomastia, changes in body composition (weight
gain, reduced muscle mass, increase in body fat), and changes in lipids, are less commonly
recognized as side effects of AD. These effects may lead to an exacerbation of potentially more
serious conditions, such as hypertension, diabetes, and coronary artery disease.55 Loss of bone
mineral density, anemia, and hair changes also may occur. Additionally, both the diagnosis of
prostate cancer and the hormonal therapy can cause psychological distress. These side effects
need more systematic study in clinical trials. Such studies would provide well-defined side effect
profiles for better informing physicians of the far-reaching consequences of AD therapy and
improve the awareness that they should incorporate into routine practice strategies for preventing
and managing toxicities.56
AD has been shown to have a negative impact on health-related quality of life (HRQOL) in
patients with asymptomatic lymph node positive prostatic carcinoma. One study showed
significantly worse sexual, emotional, and physical function, with more hot flushes and worse
overall HRQOL (using the Functional Assessment of Cancer Therapy-General [FACT-G] scale) in
those patients, compared with patients receiving no therapy.57 To address HRQOL, RTOG 0534
will compare the treatment arms for differences in prostate cancer HRQOL outcomes (as
measured by change over time in the Expanded Prostate Cancer Index Composite [EPIC]) in a
subset of patients in each treatment arm. The EPIC is a prostate cancer HRQOL instrument that
measures a broad spectrum of urinary, bowel, sexual, and hormonal symptoms related to
radiotherapy and hormonal therapy.57
Studies also suggest selective associations with decline in testosterone and estradiol, including
cognitive performance. The cognitive domains of verbal fluency, visual recognition, and visual
memory were associated with decline in estradiol. Visual-motor slowing and slowed reaction
times in some attentional domains including working memory, impaired delayed recall, and
recognition speed of letters were associated with decline in testosterone during AD.58-59Cognition
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RTOG 0534
will be measured by a brief battery of reliable and valid tests previously tested for feasibility within
the RTOG,60 including the Hopkins Verbal Learning Test-Revised (HVLT-R)61-62 for memory, the
Controlled Oral Word Association Test (COWAT) for verbal fluency,63 the Trail Making Test Part
A for cognitive processing speed, and the Trail Making Test Part B for executive function.
1.5.1
1.6
The incidence of suicide among older men with prostate cancer is higher than previously
recognized. Depression, recent diagnosis, pain, and being foreign-born are important clinical
correlates.64 The results of several recent studies suggest that estrogen and testosterone play an
important role in the modulation of mood and cognitive function in women and men, and
preliminary evidence indicates that these hormones may also modulate the levels of beta-amyloid
(Abeta),65 a 4 Kilo Dalton peptide that is likely to be involved in the pathogenesis of cognitive
disorders such as Alzheimer's disease. A recent study assessed the physiological and clinical
effects of reversible chemical castration on 40 men with prostate cancer who were treated with
androgen blockade therapy (flutamide and leuprolide) for 36 weeks and subsequently followed
for another 18 weeks after treatment was discontinued.66 The results indicated that chemical
castration is associated with a significant rise in the plasma levels of Abeta and, clinically, with
increased depression and anxiety scores. The discontinuation of treatment is associated with
better cognitive performance, most noticeably of verbal memory. The performance of subjects on
a word list memory test was negatively correlated with plasma levels of Abeta, but the clinical
significance of this finding remains to be determined. Depression and mood will be measured in
this study by the Hopkins Symptom Checklist (HSCL-25). Serum levels of beta-amyloid will be
assessed at the same time points as the HSCL-25 and the neurocognitive test battery;
associations among Abeta levels and cognitive tests will be evaluated.
Urinary symptom and function assessment
Urinary function assessment has become a mainstay of routine clinical practice using the
American Urological Association Symptom Index Score (AUA SI) or International Prostate
Symptom Score (IPSS) questionnaire.80 This questionnaire is routinely administered before and
after radiotherapy, and treatment decisions, such as the administration of an alpha-blocker, are
often based on the results. We propose to collect urinary symptom data on the entire patient
cohort (not just those in the HRQOL subset) to explore the relationship between the
questionnaire parameters and urinary morbidity using the CTCAE v. 3.0 (see section 7.7)
grading system.
Cost Effectiveness
Almost every incremental improvement in survival or progression-free survival comes at a cost.
The cost is both financial and experienced in terms of quality of life. Measurement of primary
outcomes such as freedom from progression and the most important aspects of human
functioning and quality of life will permit a summary equation allowing for differences in quality of
life, clinical outcomes, and cost to be incorporated into one equation. This equation is the Quality
Adjusted Life Year (QALY) and a study-specific modification, the Quality Adjusted Freedom From
Progression Year (QAFFPY). The QALY has been modified in a similar manner for different
treatments where survival is not the primary outcome. Much of the work in modifying the QALY
began in ophthalmology, where sight-years, not life-years, are the outcome of interest. Examples
of modifications to the QALY have included incremental cost per vision-year gained to assess the
cost effectiveness of photodynamic therapy with verteporfin for age-related macular
degeneration,66 costs per sight-year saved with screening for diabetic retinopathy,67 cost-utility
analysis for treatments of retinal detachment associated with severe proliferative
vitreoretinopathy,68 and the cost-utility of cataract surgery.69 However, the QALY has been used
in other studies where survival is not the primary outcome of interest, such as the costeffectiveness of memantine in the treatment of patients with moderately severe to severe
cognitive impairment from Alzheimer's70 and cochlear implantation for patients unable to gain
effective speech recognition with hearing aids.71 We will model costs using Medicare
reimbursement and measure utilities with the brief five-item EuroQol (EQ-5D).
The EQ-5D is a method for obtaining valuations (utilities) of health-related quality of life (HRQOL)
to be used as an adjustment to survival and in the cost-utility analysis. Developed in 1987, the
EQ-5D is used by investigators and the pharmaceutical industry throughout the United States,
Europe, and Asia. It is one of only several measures recommended for use in cost-effectiveness
analyses by the Washington Panel on Cost Effectiveness in Health and Medicine.72 The EQ-5D
instrument is intended to complement other forms of QOL measures, and it has been
purposefully developed to generate a generic cardinal index of health, thus giving it considerable
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RTOG 0534
potential for use in economic evaluation. The argument by some that a generic measure does
not capture some of the disease- or treatment-specific concerns of a given study misses the
point. This cost-effectiveness analysis is being done for purposes of exploring the means to
inform macro (health policy, payer) decision making, not micro (individual) decision making. The
findings from the disease-specific QOL instruments and treatment-related side effect QOL
instruments described above will help inform individual decision making. The role of the EQ-5D is
to measure HRQOL at a macro level, in the same metric as it has been measured across
numerous diseases, including cancer.
This instrument gives us the ability to compare across and within diseases the “big picture” of
what the experts who developed the EQ-5D considered the primary health states of interest to
humans: mobility, self care, usual activities, pain/discomfort, and anxiety/depression. Further,
there is no standardized measure to assess and compare disease-specific utilities across or
within diseases. Unlike the EQ-5D, the actual content of standard gamble (SG) and time tradeoff (TTO) methods vary widely among studies and are subject to wide variations in amount and
type of information presented, message framing, and visual aids, making replication of utilities
with the SG or TTO extremely difficult. Therefore, using the EQ-5D, an exploratory aim is to
evaluate the cost-utility of the treatment arm demonstrating the most significant benefit (in terms
of the primary outcome), in comparison to other widely accepted cancer and non-cancer
therapies (see Table 2 below). We will also assess cost-utility among the arms to assess which
therapy dominates. We will assess the value added of the summary score known as a Quality
Adjusted Life Year (QALY), and for this study the Quality Adjusted FFP Year, that combines
benefits of duration of freedom from progression (FFP) and decrements of quality of life with
financial cost of increasingly aggressive and costly therapy.
Table 2: Common Medical Interventions Ranked by Incremental Cost-Effectiveness
$U.S./Life Year Gained73
Intervention
Incremental Cost-effectiveness
($U.S.)
Liver transplantation compared with medical management 237,000
Mammography, age < 50 yrs.
232,000
1.6.1
Dialysis compared with medical management
50,000
Drug therapy for moderate hypertension
Mammography screening for breast cancer in patients
aged 50-75 years
ABMT compared with salvage CT for Hodgkin’s recurrent
after MOPP-ABV
Induction CT and standard RT on RTOG trials for NonSmall Cell Carcinoma of the Lung
32,600
20,000-50,000
21,100
7,500-18,50073
The EQ-5D has been used across numerous disease sites, including cancer. For example, the
EQ-5D mean score for 95 patients with NSCLC (93% male, mean age 62 years) was 0.58 (SD
0.32) as measured by the questionnaire and 0.58 (SD 0.20) as measured by the visual analogue
scale (VAS) version.75 The EQ-5D has been used to assess QALYs and the economic value of
prostate cancer screening,76 and treatment of pain related to prostate cancer metastasis.77
Further, the EQ-5D was used in a recent study to estimate the economic value of the welfare loss
due to prostate cancer pain by estimating the extent to which pain affects health-related quality of
life among patients with prostate cancer. Health status and economic outcomes were modeled
among a well-defined population of 200,000 Swedish prostate cancer patients. Health utility
ratings (using the EQ-5D) were obtained from a subset of 1,156 of the prostate cancer patients. A
descriptive model showed that optimal treatment that would reduce pain to zero during the whole
episode of disease would add on average 0.85 quality-adjusted life years (QALY) to every man
with prostate cancer; the economic value of this welfare loss due to prostate cancer pain was
approximately $121,240,000 per year.78
Quality-Adjusted Survival and Freedom from Progression
Quality-adjusted survival and freedom from progression can be defined in the same manner, by
the weighted sum of different time episodes added up to a total quality-adjusted life-year or
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RTOG 0534
1.6.2
1.6.3
2.0
freedom from progression–year [U= sum of quality (qi) of health states K times the duration (si)
spent in each health state.79
Cost-Effectiveness and Cost-Utility
Cost-utility will be analyzed for planned publication at two time points: 1) at 1 year posttherapy, looking at initial treatment costs and quality of life and 2) at five years post-therapy.
The cost-utility analysis will be done after the primary endpoint results are published.
Measurement of Costs
Direct medical costs fall into three categories: 1) initial therapy costs; 2) costs of managing the
most common side effects as determined by this study; and 3) costs of managing recurrence.
Costs for external beam radiotherapy will be determined using CPT coding and Medicare
reimbursement rates. Costs of common management strategies of the most common side
effects documented in this study (e.g., Imodium® for diarrhea) will be estimated from regional
costs per unit. Costs for managing recurrence will assume the following salvage therapies:
hormone therapy and chemotherapy. Costs will include professional fees, cost/inpatient day,
drugs, and supplies. Direct non-medical costs such as the cost of work lost or of transportation
will not be measured. Incremental differences in costs and outcomes will be compared for the
different alternatives and for the dominant alternative to other established therapies
documented in the literature.
OBJECTIVES
2.1
Primary Objectives
2.1.1
To determine whether the addition of NC-STAD to PBRT improves freedom from progression
(FFP) [maintenance of a PSA less than the nadir+2 ng/mL, absence of clinical failure and
absence of death from any cause] for 5 years, over that of PBRT alone in men treated with
salvage RT after radical prostatectomy;
2.1.2
To determine whether NC-STAD+PLNRT+PBRT improves FFP over that of NC-STAD+PBRT
and PBRT alone in men treated with salvage RT after radical prostatectomy.
2.2
Secondary Objectives (11/23/11)
2.2.1
To compare the rates of a PSA ≥ 0.4 ng/mL and rising at 5 years after randomization
(secondary biochemical failure endpoint), the development of hormone refractory disease (3
rises in PSA during treatment with salvage androgen deprivation therapy), distant metastasis,
cause-specific mortality and overall mortality;
2.2.2
To compare acute and late morbidity based on CTCAE, v. 3.0;
2.2.3
To measure the expression of cell kinetic, apoptotic pathway, and angiogenesis-related genes
in archival diagnostic tissue to better define the risk of FFP, distant failure, cause-specific
mortality, and overall mortality after salvage radiotherapy for prostate cancer, independently of
conventional clinical parameters now used;
2.2.4
To quantify blood product–based proteomic and genomic (single nucleotide polymorphisms)
patterns, and urine-based genomic patterns before and at different times after treatment to
better define the risk of FFP, distant failure, cause-specific mortality, and overall mortality after
salvage radiotherapy for prostate cancer, independently of conventional clinical parameters
now used;
2.2.5
To assess the degree, duration, and significant differences of disease-specific health related
quality of life (HRQOL) decrements among treatment arms; it is hypothesized that QOL as
measured by the EPIC will significantly worsen by the increasing aggressiveness of treatment
and that cognition as measured by the neurocognitive test battery (the HVLT-R, Trail Making
Test, parts A & B, and the COWAT) will be significantly worse in the arms with NC-STAD.
2.2.6
To assess whether mood is improved and depression is decreased with the more aggressive
therapy if it improves FFP; it is hypothesized that QOL as measured by the HSCL-25 will
significantly improve with the increasing aggressiveness of treatment due to improved FFP.
2.2.7
An exploratory aim is to assess whether an incremental gain in FFP and survival with more
aggressive therapy outweighs decrements in the primary generic domains of health related
quality of life (i.e., mobility, self care, usual activities, pain/discomfort, and anxiety/depression).
This aim is reported as the Quality Adjusted FFP Year (QAFFPY) and as the Quality Adjusted
Life Year (QALY). The QAFFPY and QALY will be compared among treatment arms and to the
literature as described in Section 1.6.
2.2.8
An exploratory aim is to evaluate the cost-utility of the treatment arm demonstrating the most
significant benefit (in terms of the primary outcome) in comparison with other widely accepted
cancer and non-cancer therapies. Cost-utility will be assessed by the EQ-5D among treatment
arms to determine which therapy dominates.
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RTOG 0534
2.2.9
2.2.10
2.2.11
An exploratory aim is to assess associations between serum levels of beta-amyloid (Abeta) and
measures of cognition (as measured by the HVLT-R, Trail Making Tests, parts A & B, or the
COWAT) and mood and depression (as measured by the HSCL-25).
To collect paraffin-embedded tissue blocks, serum, plasma, urine, and whole blood for future
translational research analyses
An exploratory aim is to assess the relationship(s) between the American Urological
Association Symptom Index (AUA SI) and urinary morbidity using the CTCAE v. 3.0 grading
system.
3.0
PATIENT SELECTION
NOTE: PER NCI GUIDELINES, EXCEPTIONS TO ELIGIBILITY ARE NOT PERMITTED.
3.1
Conditions for Patient Eligibility (11/23/11)
3.1.1
Adenocarcinoma of the prostate treated primarily with radical prostatectomy, pathologically
proven to be lymph node negative by pelvic lymphadenectomy (N0) or lymph node status
pathologically unknown (undissected pelvic lymph nodes [Nx]), i.e. lymph node dissection is not
required;
3.1.1.1
Any type of radical prostatectomy will be permitted, including retropubic, perineal,
laparoscopic or robotically assisted. If performed, the number of lymph nodes removed
per side of the pelvis and the extent of the pelvic lymph node dissection (obturator vs.
extended lymph node dissection) should be noted. There is no time limit for the date of
radical prostatectomy.
3.1.2
A post-radical prostatectomy entry PSA of ≥ 0.1 and < 2.0 ng/mL at least 6 weeks (45 days)
after prostatectomy and within 30 days of registration;
3.1.3
One of the following pathologic classifications:
3.1.3.1
T3N0/Nx disease with or without a positive prostatectomy surgical margin; or
3.1.3.2
T2N0/Nx disease with or without a positive prostatectomy surgical margin;
3.1.4
Prostatectomy Gleason score of 9 or less;
3.1.5
Zubrod Performance Status of 0-1;
3.1.6
Age ≥ 18;
3.1.7
No distant metastases, based upon the following minimum diagnostic workup:
3.1.7.1
History/physical examination (including digital rectal exam) within 8 weeks (60 days) prior to
registration;
3.1.7.2
A CT scan of the pelvis (with contrast if renal function is acceptable; a noncontrast CT is
permitted if the patient is not a candidate for contrast) or MRI of the pelvis within 120 days
prior to registration;
3.1.7.3
Bone scan within 120 days prior to registration; if the bone scan is suspicious, a plain x-ray
and/or MRI must be obtained to rule out metastasis.
3.1.8
Adequate bone marrow function, within 90 days prior to registration, defined as follows:
 Platelets ≥ 100,000 cells/mm3 based upon CBC;
 Hemoglobin ≥ 10.0 g/dl based upon CBC (Note: The use of transfusion or other
intervention to achieve Hgb ≥ 10.0 g/dl is recommended).
3.1.9
AST or ALT < 2 x the upper limit of normal within 90 days prior to registration;
3.1.10
Serum total testosterone must be ≥ 40% of the lower limit of normal (LLN) of the assay used
(testosterone ÷ LLN must be ≥ 0.40) within 90 days prior to registration (Note: Patients who
have had a unilateral orchiectomy are eligible as long as this requirement is met);
3.1.11
Patients must sign a study-specific informed consent prior to study entry.
3.2
3.2.1
3.2.2
3.2.3
3.2.4
Conditions for Patient Ineligibility (11/23/11)
A palpable prostatic fossa abnormality/mass suggestive of recurrence, unless shown by biopsy
under ultrasound guidance not to contain cancer;
N1 patients are ineligible, as are those with pelvic lymph node enlargement ≥ 1.5 cm in
greatest dimension by CT scan or MRI of the pelvis, unless the enlarged lymph node is
sampled and is negative;
Androgen deprivation therapy started prior to prostatectomy for > 6 months (180 days)
duration. Note: The use of finasteride or dutasteride (±tamsulosin) for longer periods prior to
prostatectomy is acceptable;
Androgen deprivation therapy started after prostatectomy and prior to registration (Note: The
use of finasteride or dutasteride (±tamsulosin) after prostatectomy is not acceptable - must be
stopped within 3 months after prostatectomy. Androgen deprivation therapy must be stopped
within 3 months after prostatectomy);
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RTOG 0534
3.2.5
3.2.6
3.2.7
3.2.8
3.2.9
3.2.10
3.2.10.1
3.2.10.2
3.2.10.3
3.2.10.4
3.2.10.5
3.2.10.6
3.2.10.7
3.2.10.8
3.2.11
Neoadjuvant chemotherapy before or after prostatectomy;
Prior chemotherapy for any other disease site if given within 5 years prior to registration;
Prior cryosurgery or brachytherapy of the prostate; prostatectomy should be the primary
treatment and not a salvage procedure;
Prior pelvic radiotherapy;
Prior invasive malignancy (except non-melanomatous skin cancer) or superficial bladder
cancer unless disease free for a minimum of 5 years [for example, carcinoma in situ of the oral
cavity is permissible];
Severe, active co-morbidity, defined as follows:
History of inflammatory bowel disease;
History of hepatitis B or C; Blood tests are not required to determine if the patient has had
hepatitis B or C, unless the patient reports a history of hepatitis.
Unstable angina and/or congestive heart failure requiring hospitalization within the last 6
months;
Transmural myocardial infarction within the last 6 months;
Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration;
Chronic Obstructive Pulmonary Disease exacerbation or other respiratory illness requiring
hospitalization or precluding study therapy at the time of registration;
(01/8/09)Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects; AST
or ALT are required (see Section 3.1.9); note, however, that laboratory tests for coagulation
parameters are not required for entry into this protocol.
Acquired Immune Deficiency Syndrome (AIDS) based upon current CDC definition; Note,
however, that HIV testing is not required for entry into this protocol. The need to exclude
patients with AIDS from this protocol is necessary because the treatments involved in this
protocol may result in increased toxicity and immunosuppression.
Prior allergic reaction to the study drug(s) involved in this protocol.
4.0
PRETREATMENT EVALUATIONS/MANAGEMENT
Note: This section lists baseline evaluations needed before the initiation of protocol treatment that do not
affect eligibility.
4.1
Required Pretreatment Evaluations/Management (1/8/09)
4.1.1
A measure of urinary function is the American Urological Association Symptom Index Score
(AUA SI) or International Prostate Symptom Score (IPSS),80 which is now routinely the basis for
treatment decisions. This scoring system has been established as a measure of radiation
morbidity in patients treated for prostate cancer.81-84 The American Urological Association
Symptom Index (AUA SI) will be administered to all protocol patients. The AUA SI
questionnaire should be completed within 30 days prior to the start of treatment.
4.1.2
Representative H & E stained slides from the prostatectomy specimen that document the
Gleason score, extraprostatic extension, margin status, lymph node negativity, and seminal
vesicle status for central pathology review (see Section 10.2).
4.2
Highly Recommended Pretreatment Evaluations/Management (11/23/11)
Within 30 days prior to the start of any protocol treatment:
4.2.1
Baseline alkaline phosphatase;
4.2.2
Some form of apical prostate bed localization, in addition to a non-contrast CT simulation, is
recommended, but not required. The methods include CT scan with urethrogram at the time of
simulation or MRI (see Section 6.3.1) simulation to localize the inferior aspect of the prostate
bed.
5.0
REGISTRATION PROCEDURES (12/10/13)
Access requirements for OPEN and TRIAD
Site staff will need to be registered with CTEP and have a valid and active CTEP Identity and Access
Management (IAM) account. This is the same account (user id and password) used for the CTSU
members' web site. To obtain an active CTEP-IAM account, go to https://eapps-ctep.nci.nih.gov/iam.
NOTE: It is mandatory that the treating physician determine the radiation therapy technique (3D-CRT vs.
IMRT) to be used prior to the site registering the patient.
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RTOG 0534
5.1
5.1.1
5.1.2
5.2
5.2.1
5.2.2
5.3
Pre-Registration Requirements for 3D-CRT Treatment Approach (12/10/13)
Only institutions that have met the technology requirements and that have provided the
baseline physics information that are described in 3DCRT Quality Assurance Guidelines may
enter patients onto this study..
The new Facility Questionnaire (one per institution, available on the RPC web site at
http://rpc.mdanderson.org/rpc/) or a modification to your existing Facility Questionnaire on file is
to be sent to RTOG for review prior to entering any cases. RTOG Headquarters will notify the
institution when all requirements have been met and the institution is RT credentialed to enter
patients onto this study.
Pre-Registration Requirements for IMRT Treatment Approach (12/10/13)
In order to utilize IMRT on this study, the institution must have met specific technology
requirements and have provided baseline physics information. Instructions for completing these
requirements or determining if they already have been met are available on the Radiological
Physics Center (RPC) web site. Visit http://rpc.mdanderson.org/rpc and select “Credentialing”
and “Credentialing Status Inquiry”.
Institutions that previously have been credentialed for one IMRT delivery technique (e.g.,
standard gantry mounted linear accelerator using fixed gantry angles) must repeat the
credentialing process when they change to a different technology (e.g. tomotherapy or volume
delivery methods like RapidArc or VMAT).
An IMRT phantom study with the RPC must be successfully completed (if the institution has not
previously met this credentialing requirement on another RTOG IMRT prostate or head and
neck study). Instructions for requesting and irradiating the phantom are available on the RPC
web site at http://rpc.mdanderson.org/rpc/; select “Credentialing” and “RTOG”. Upon review
and successful completion of the phantom irradiation, the RPC will notify both the registering
institution and RTOG Headquarters that the institution has completed this requirement.
Subsequently, RTOG Headquarters will notify the institution that the IMRT credentialing
requirement has been met.
The institution or investigator must update or complete a new IMRT facility questionnaire
(available on the RPC web site at http://rpc.mdanderson.org/rpc/) and send it to RTOG for
review prior to entering any cases. RTOG Headquarters will notify the institution when all
requirements have been met and the institution is RT credentialed to enter patients onto this
study.
Digital RT Data Submission to RTOG Using TRIAD (12/10/13)
This trial will not utilize the services of the ITC for dosimetry digital treatment data
submission. TRIAD, the American College of Radiology’s (ACR) image exchange
application that is used by the Radiation Therapy Oncology Group (RTOG), will be used.
TRIAD provides sites participating in RTOG clinical trials a secure method to transmit
DICOM RT and other objects. TRIAD anonymizes and validates the images as they are
transferred.
TRIAD Access Requirements:
 Site physics staff who will submit images through TRIAD will need to be registered with The
Cancer Therapy Evaluation Program (CTEP) and have a valid and active CTEP Identity and
Access Management (IAM) account. Please refer to Section 5.0 of the protocol for
instructions on how to request a CTEP-IAM account.
 To submit images, the site physics user must have been assigned the 'TRIAD site user' role
on the relevant Group or CTSU roster. RTOG users should contact your site Lead RA to be
added to your site roster. Users from other cooperative groups should follow their
procedures for assignment of roster roles.

RAs are able to submit standard of care imaging through the same method.
TRIAD Installations:
When a user applies for a CTEP-IAM account with proper user role, he/she will
need to have the TRIAD application installed on his/her workstation to be able to
submit images. TRIAD installation documentation can be found on the RTOG
website Core Lab tab.
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RTOG 0534
This process can be done in parallel to obtaining your CTEP-IAM account username and
password.
If you have any questions regarding this information, please send an e-mail to the TRIAD Support
mailbox at [email protected].
5.4
5.4.1
Regulatory Pre-Registration Requirements (12/10/13)
This study is supported by the NCI Cancer Trials Support Unit (CTSU). Prior to the recruitment
of a patient for this study, investigators must be registered members of a Cooperative Group.
Each investigator must have an NCI investigator number and must maintain an “active”
investigator registration status through the annual submission of a complete investigator
registration packet (FDA Form 1572 with original signature, current CV, Supplemental
Investigator Data Form with signature, and Financial Disclosure Form with original signature) to
the Pharmaceutical Management Branch (PMB), CTEP, DCTD, NCI. These forms are available
on the CTSU registered member web site or by calling the PMB at 240-276-6575 Monday
through Friday between 8:30 a.m. and 4:30 p.m. Eastern time.
Each investigator or group of investigators at a clinical site must obtain IRB approval for this
protocol and submit IRB approval and supporting documentation to the CTSU Regulatory
Office before they can enroll patients. Study centers can check the status of their registration
packets by querying the Regulatory Support System (RSS) site registration status page of the
CTSU member web site by entering credentials at https://www.ctsu.org.
5.4.2
5.4.2.1
5.4.3
5.4.3.1
Requirements for RTOG 0534 site registration:
 CTSU IRB Certification
 CTSU IRB/Regulatory Approval Transmittal Sheet
 CTSU RT Facilities Inventory Form (if applicable)
NOTE: Per NCI policy all institutions that participate on protocols with a radiation therapy
component must participate in the Radiological Physics Center (RPC) monitoring program. For
non-lead group institutions an RT Facilities Inventory Form must be on file with CTSU. If this
form has been previously submitted to CTSU it does not need to be resubmitted unless
updates have occurred at the RT facility.
In addition to the requirements noted above, ALL institutions must fax copies of the
documentation below to the CTSU Regulatory Office (215-569-0206); study-related regulatory
documentation also may be e-mailed to the CTSU at [email protected]. This
must be done prior to registration of the institution’s first case:
 IRB/REB approval letter;
 IRB/REB approved consent (English and native language versions*)
*Note: Institutions must provide certification/verification of IRB/REB consent translation to
RTOG Headquarters (See “Non-English Speaking Canadian and Non-North American
Institutions” below)
 IRB/REB assurance number renewal information as appropriate
Non-English Speaking Canadian and Non-North American Institutions
Translation of documents is critical. The institution is responsible for all translation costs. All
regulatory documents, including the IRB/REB approved consent, must be provided in
English and in the native language. Certification of the translation is optimal but due to the
prohibitive costs involved RTOG will accept, at a minimum, a verified translation. A verified
translation consists of the actual REB approved consent document in English and in the
native language, along with a cover letter on organizational/letterhead stationery that
includes the professional title, credentials, and signature of the translator as well as signed
documentation of the review and verification of the translation by a neutral third party. The
professional title and credentials of the neutral third party translator must be specified as
well.
Pre-Registration Requirements FOR CANADIAN INSTITUTIONS
Prior to clinical trial commencement, Canadian institutions must complete and fax (215-5690206) or e-mail ([email protected]) the following forms to the CTSU
Regulatory Office:
 Health Canada’s Therapeutic Products Directorates’ Clinical Trial Site Information Form,
 Qualified Investigator Undertaking Form, and
 Research Ethics Board Attestation Form.
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RTOG 0534
5.4.4
5.4.4.1
5.4.4.2
5.5
5.5.1
Pre-Registration Requirements FOR NON-CANADIAN INTERNATIONAL INSTITUTIONS
For institutions that do not have an approved LOI for this protocol:
International sites must submit an LOI to RTOG Headquarters to receive approval to
participate in this trial. For more details see link below:
http://www.rtog.org/Researchers/InternationalMembers/LetterofIntent.aspx .
For institutions that have an approved LOI for this protocol:
All requirements indicated in your LOI Approval Notification must be fulfilled prior to enrolling
patients to this study.
Registration (12/10/13)
OPEN Registration Instructions
Patient registration can occur only after evaluation for eligibility is complete, eligibility criteria have
been met, and the study site is listed as ‘approved’ in the CTSU RSS. Patients must have signed
and dated all applicable consents and authorization forms.
Patient enrollment will be facilitated using the Oncology Patient Enrollment Network (OPEN).
OPEN is a web-based registration system available on a 24/7 basis. All site staff (RTOG and
CTSU Sites) will use OPEN to enroll patients to this study. OPEN can be accessed at
https://open.ctsu.org or from the OPEN tab on the CTSU members’ web site
https://www.ctsu.org.
Prior to accessing OPEN site staff should verify the following:
 All eligibility criteria have been met within the protocol stated timeframes. Site staff should
use the registration forms provided on the group or CTSU web site as a tool to verify
eligibility.
 All patients have signed an appropriate consent form and HIPPA authorization form (if
applicable).
Access requirements for OPEN:
 See Section 5.0 for obtaining a CTEP-IAM account.
 To perform registrations, the site user must have been assigned the 'Registrar' role on the
relevant Group or CTSU roster.
 To perform registrations on protocols for which you are a member of the RTOG, you must
have an equivalent 'Registrar' role on the RTOG roster. Role assignments are handled
through the Groups in which you are a member.
 To perform registrations to trials accessed via the CTSU mechanism (i.e., non-Lead Group
registrations) you must have the role of Registrar on the CTSU roster. Site and/or Data
Administrators can manage CTSU roster roles via the new Site Roles maintenance feature
under RSS on the CTSU members' web site. This will allow them to assign staff the
"Registrar" role.
 NOTE: If you are enrolling as a non-RTOG member site: Prior to beginning the enrollment,
call the RTOG Randomization desk at 215-574-3191 or 215-574-3192 to obtain an RTOG,
non-Lead Group, site-specific institution number.
The OPEN system will provide the site with a printable confirmation of registration and treatment
information. Please print this confirmation for your records.
Further instructional information is provided on the CTSU members' web site OPEN tab or within
the OPEN URL. For any additional questions contact the CTSU Help Desk at 1-888-823-5923 or
[email protected].
In the event that the OPEN system is not accessible, participating sites can contact RTOG web
support for assistance with web registration: [email protected] or call the RTOG Registration
Desk at (215) 574-3191, Monday through Friday, 8:30 a.m. to 5:00 p.m. ET. The registrar will ask
the site to fax in the eligibility checklist and will need the registering individual’s e-mail address
and/or return fax number. This information is required to assure that mechanisms usually
triggered by the OPEN web registration system (e.g. drug shipment and confirmation of
registration) will occur.
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RTOG 0534
6.0
RADIATION THERAPY (12/10/13)
This trial will not utilize the services of the ITC for dosimetry digital treatment data submission.
PRIOR TO ENROLLING PATIENTS, please see Section 5.3 for information on installing TRIAD for
submission of digital RT data.
Note: Intensity Modulated RT (IMRT) is allowed for this study. See Section 5.0 for pre-registration
requirements for IMRT and 3D-CRT treatment techniques.
Radiotherapy will start within 42 days (+/-14 days) after registration in Arm 1 and 60 days (+/-14
days) after starting LHRH agonist treatment in Arms 2 and 3.
Arm 1, PBRT Alone: PBRT 64.8-70.2 Gy (1.8 Gy per fraction)
Arm 2, PBRT + NC-STAD: PBRT 64.8-70.2 Gy (1.8 Gy per fraction) + NC-STAD for 120-180 days,
beginning 60 days (+/- 14 days) before RT
Arm 3, PLNRT + PBRT + NC-STAD: PLNRT to 45 Gy (1.8 Gy per fraction) and PBRT to 64.8-70.2 Gy
(1.8 Gy per fraction). NC-STAD for 120-180 days, beginning 60 days (+/- 14 days) before RT
6.1
6.2
6.3
6.3.1
Dose Specifications (X/XX/11)
Radiotherapy will start within 42 days (+/-14 days) of registration in Arm 1 and 60 days (+/-14
days) after starting LHRH agonist treatment in Arms 2 and 3. Radiotherapy dose will be specified
to the Planning Target Volume (PTV), as described in section 6.4. For the treatment methods
outlined for prostate bed RT (3D-CRT, and IMRT), ≥ 95% of the PTV should receive the
prescribed dose. The total dose to the prostate bed for all treatment arms is 64.8-70.2 Gy at 1.8
Gy per fraction. IMRT is strongly encouraged over 3D-CRT.
Technical Factors [Equipment, energies]
Megavoltage equipment is required with effective photon energies ≥ 6 MV.
Localization, Simulation, and Immobilization (11/23/11)
3D-Conformal Radiotherapy (3D-CRT) or IMRT
A urethrogram or MRI is recommended, but not required, to establish the most inferior portion
of the prostate bed. Use of contrast, other than for the urethrogram, is discouraged. The
placement of contrast in the rectum may cause the rectum to appear more anterior than it will
be during treatment. Simulation should be with the rectum as empty as possible (an enema 1-2
hours prior to simulation) and with a moderately full bladder (the patient should not be
uncomfortable at simulation and probably will have more difficulty maintaining a full bladder
during treatment). An overly distended rectum can introduce a systematic positioning error that
may increase the probability of missing the CTV. This is the reasoning behind an enema before
the planning CT scan; although other methods, such as the use of a hollow (robnel) catheter to
evacuate flatus to reduce the size of the rectum may accomplish the same result.
Immobilization of the hips and feet using a cradle should be considered.
A treatment planning CT scan will be required to define the clinical and planning target
volumes, and the critical normal structures. The treatment planning CT will be acquired with the
patient set up in the same position as for daily treatments. Each patient will be positioned in the
supine position. Prone positioning for treatment is not permitted. Rectal balloons for planning
and treatment are not permitted. The CT scan of the pelvis should start at or above the iliac
crest down to below the perineum (below the ischial tuberosities). All tissues to be irradiated
must be included in the CT scan. CT scan thickness should be ≤ 0.3 cm through the region that
contains the target volumes. The regions above and below the target volume region may be
scanned with slice thickness ≤ 1.0 cm.
6.4
Treatment Planning/Target Volumes (12/10/13)
6.4.1
Prostate Bed Planning for 3D-CRT
The definition of volumes will be in accordance with ICRU Report #50: Prescribing, Recording,
and Reporting Photon Beam Therapy. Please see Section 6.8.2 for common contouring
mistakes.
6.4.1.1
CTVp (1/8/09) (3/24/10)
Contrast may be used for simulation but can distort the anatomy slightly and so is not
recommended. The bladder should be reasonably full for simulation, keeping in mind that
patients may not be able to maintain as full a bladder during radiotherapy. Having a
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RTOG 0534
somewhat full bladder at simulation ensures that the CTVp will be of maximal dimensions.
The seminal vesicles or remnants thereof, if identified on CT or MRI as being present, will
receive the full dose. The immediate periprostatic bed surgical clips should receive the full
dose. The CTVp will extend from the top of the penile bulb inferiorly, or 1.5 cm below the
urethrogram peak if done, to just above the pubic symphysis superiorly (at least for the
anterior-most portion of the bladder). Laterally, the CTVp will extend from the medial edge of
one obturator internus muscle to the other. Anteriorly, the CTVp will include the entire
bladder neck until above the pubic symphysis, where a gradual reduction off of the anterior
bladder is made. Superiorly, above the pubic symphysis, at least the posterior 2 cm of
bladder should be included in the CTVp, as well as the area between the bladder and
rectum, to the anterior rectal wall. The CTVp should extend superiorly to cover any clips in
the seminal vesicle bed and the seminal vesicle remnants if present and should extend at
least 2 cm above the pubic symphysis. Posteriorly, the CTVp is defined by the anterior-most
aspects of the anus-rectum. The CTVp may be increased (not decreased) beyond these
limits based on pre-prostatectomy imaging information.
A consensus definition of the prostate bed85 and an anatomically-based description86 should
be considered in defining the CTVp. There has been considerable variability in how the
prostate bed has been defined in the past. Although consensus definitions are not based on
clinical outcome, they are extremely valuable in making the transition from conventional to
conformal volumes. The consensus definition is not much different than the CTVp originally
described above, but subtle differences are evident and should be considered. Either CTVp
definition will be accepted in this clinical trial.
6.4.1.2
1) Superiorly: The prostatic fossa CTV (CTVp) should extend superiorly from the level of the
caudal vas deferens remnant. In some cases, the vas deferens remnant may be difficult
to visualize. In the absence of gross disease or seminal vesicle remnants, the superior
limit of the CTVp should extend at least 2 cm and need not extend more than 3-4 cm
above the level of the pubic symphysis. The consensus definition calls for “inclusion of
the seminal vesicle remnants, if present, in the CTVp if there is pathologic evidence of
their involvement. However, inclusion of any seminal vesicle remnants seen is
recommended.
2) Inferiorly: The CTVp should extend inferiorly to > 8-12 mm inferior to vesicourethral
anastomosis (VUA). With axial CT imaging, the VUA can often be seen in the retropubic
region as one slice below the most inferior urine-containing image (the bladder must be
modestly full). Magnetic resonance (MR) imaging defines this landmark more clearly
with the hyperintense urine signal on T2 images. Inferiorly, the border of the CTVp
should be at least 8-12 mm below the VUA. A sagittal reconstruction facilitates
identification of the position of the VUA and the inferior border of the CTVp below it. If
visualization of the VUA is problematic due to image quality or surgical clip artifacts, the
inferior limit of the CTVp can extend to a level just above the penile bulb (same border
as described above). It should be noted that there was considerable discussion about
this definition versus extending the inferior border of the CTVp to just above the penile
bulb; both definitions were deemed acceptable.
3) Anteriorly: Below the superior border of the pubic symphysis, the anterior border is at the
posterior aspect of the pubis. The CTVp extends posteriorly to the rectum where it may
be concave at the level of the VUA. At this level the lateral border extends to the levator
ani. Above the pubic symphysis the anterior border should encompass the posterior 12 cm of the bladder wall at the minimum and posteriorly it is bounded by the
mesorectal fascia. At this level the lateral border is the sacrorectogenitopubic fascia.
This is not well-defined in textbooks. If in question, the lateral border should extend to
the obturator internus muscle.
4) Posteriorly: The CTVp extends posteriorly to the anterior rectal wall, but may be
somewhat concave around the anterior-lateral aspect of the rectum to adequately
encompass the prostate bed.
PTVp (11/23/11)
The PTVp margins should be a minimum of 0.8 cm and a maximum of 1.5 cm in all
dimensions. A reduction of the PTVp margin from 0.8 cm to ≥ 0.6 cm to minimize rectal
exposure will be considered a variation acceptable. A posterior margin of < 0.6 cm will be
considered an unacceptable deviation. A margin for penumbra for 3D-CRT, usually 0.5–0.7
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RTOG 0534
6.4.1.3
6.4.2
6.4.2.1
6.4.2.2
cm beyond the PTVp should be added such that ≥ 95% of the PTVp receives the prescribed
dose (64.8-70.2 Gy); an acceptable variation will be noted if < 95% to 90% of the PTVp
receives the prescribed dose, and an unacceptable deviation will be noted if < 90% of the
PTVp receives the prescribed dose. Care should be taken to conform the prescribed dose
as closely to the PTVp as possible, so as to avoid including the entire width of the rectum in
the posterior blocked margin at the bladder neck-rectum interface. The maximum dose in
the PTVp above the prescribed dose will be 7%; a variation acceptable will be > 7% to ≤
12% and an unacceptable deviation will be > 12%. The planned dose between 64.8 to 70.2
will be declared after the patient is planned and all dosimetric parameters finalized.
Normal Tissue Definitions (11/23/11)
Normal tissues will be outlined as solid structures, including the rectum, bladder and femoral
heads. The penile bulb will be outlined as a reference structure. No constraints will be
placed on the penile bulb, but doses will be recorded. The rectum will be outlined from the
anterior flexion of the rectosigmoid superiorly to the ischial tuberosities inferiorly. The entire
bladder should be outlined down to the anastamosis. The DVH calculations will include
doses to the entire bladder and the bladder minus the CTVp (BladdermCTV; Section
6.4.2.2).The femoral heads should be outlined down to the region between the greater and
lesser trochanters. The planning parameters outlined below for IMRT should be used as a
guide; formal 3D-CRT normal tissue prostate bed constraints have not been the standard in
the past and are not specified here. It should be possible to come close to achieving the
constraints outlined for IMRT, at least within the variation range.
Prostate Bed Planning for IMRT
CTVp/PTVp/Normal Tissues
The CTVp and PTVp will be the same as for 3D-CRT. There is no need to add margin for
penumbra. A series of dose-volume histograms will be generated and analyzed to determine
the adequacy of the plan.
Planning Parameters (11/23/11)
The plan will be deemed acceptable under the following conditions.
PTVp: The dose marker levels for bladder and rectum have been modeled after prior studies
in men treated definitively with IMRT for prostate cancer.87-88 At least 95% of the PTVp
should receive the prescribed dose (64.8-70.2 Gy); a variation acceptable will be noted if <
95% to 90% of the PTVp receives the prescribed dose, and a deviation unacceptable will be
noted if < 90% of the PTVp receives the prescribed dose. The maximum dose within the
PTVp, above the prescribed dose, will be 15%; an acceptable variation will be > 15% to ≤
20% and an unacceptable deviation will be > 20%.
Rectum: Less than or equal to 35% and 55% of the rectum should receive ≥ 65 Gy and ≥ 40
Gy, respectively. An acceptable variation will be noted if up to an additional 10% of the rectal
volume at either cutpoint receives above the target doses specified. The inclusion of rectal
volumes beyond these constraints will be considered a secondary acceptable variation and
the extent of the variation should be recorded. In most patients, these constraints may be
easily met and every attempt should be made to achieve the best dose distribution possible.
The constraints will be harder to achieve in patients enrolled on Arm 3 (those receiving
pelvic irradiation).
Bladder: Less than or equal to 50% and 70% of the bladder minus CTVp (BladdermCTV)
should receive ≥ 65 Gy and ≥ 40 Gy, respectively. The criteria for the bladder are relaxed
because the dosimetric relationship of volume exposed to the specified marker doses is
much less clear and the bladder neck is included in the CTVp. Note that the DVH for the
entire bladder should be recorded, but the bladder - CTVp is the volume that should be used
for the calculations described here. An acceptable primary variation will be noted if up to an
additional 7.5% of the bladder volume receives above the target doses specified. The
inclusion of bladder volumes beyond these constraints will be considered an acceptable
secondary protocol variation; it will not be considered a protocol violation. In some patients,
the bladder will be relatively empty and the majority will be in the PTV.
Femoral Heads: Less than or equal to 10% of each femoral head should receive ≥ 50 Gy. A
variation will be noted if up to an additional 5.0% of either femoral head receives > 50 Gy.
Penile Bulb: The penile bulb will be outlined as a reference structure. No constraints will be
placed on the penile bulb, but doses will be recorded.
Small Bowel: See PLNRT section below.
Use of Cone Beam CT and Plan Adjustment: There may be cases in which the target and
surrounding normal tissues are found not to be reproducible relative to the simulation CT
15
RTOG 0534
6.4.3
6.4.3.1
6.4.3.2
and consequent plan. Replanning will invalidate the dosimetry and is considered a deviation.
If all attempts to reproduce bladder and rectal filling by coaching the patient do not work and
replanning is thought to be necessary, the patient should be replanned in the same supine
position with the same target volumes as specified per the randomization. The patient will
remain on the trial, despite the deviation.
Pelvic Lymph Node Radiotherapy (PLNRT) (11/23/11)
For Arm 3, the prostate bed and pelvic lymph nodes (CTVn/PTVn) will receive 45 Gy at 1.8 Gy
per fraction. Once this is completed, a reduction will be made to deliver a total dose of 64.8–
70.2 Gy at 1.8 Gy/fraction to the prostate bed (CTVp/PTVp). Planning and treatment of the
pelvic lymph nodes must be using the same method (3DCRT or IMRT) as the prostate bed
boost.
PLNRT Planning for 3D-CRT (11/23/11))
The CTVn will include the obturator, external iliac, proximal internal iliac and common iliac
nodes, estimated using the vascular structures, up to the level of L5-S1. The recommended
volumes are on the RTOG website under the “Core Lab/Contouring Atlases” menu
(http://www.rtog.org/CoreLab/ContouringAtlases/ProstatePelvicLymphNodes.aspx).
The CTVn is described as being 7 mm around the iliac vessels, carving out bowel, bladder
and bone, which translates into just contouring the iliac/obturator areas with essentially no
extra margin because of the proximity to these structures (this is well-illustrated in the
contouring Atlas). Thus, the PTVn margins described above are the margins that venture
into the potential bowel space, bladder and bone. The remainder of the CTVn, including the
prostate bed and seminal vesicle bed are as described above (section 6.4.1.1). The CTVp
will include the prostate bed (64.8 – 70.2 Gy), as described for PBRT above. The PTVn and
PTVp margins should be a minimum of 0.8 cm and a maximum of 1.5 cm in all dimensions.
A reduction of the PTV margin from 0.8 cm to ≥ 0.6 cm to minimize rectal exposure will be
considered an acceptable variation. A posterior margin of < 0.6 cm will be considered an
unacceptable deviation. A margin for penumbra (usually 0.5–0.7 cm beyond the PTVs for
3D-CRT) should be added such that ≥ 95% of the PTVs receive the prescribed dose; an
acceptable variation will be noted if < 95% to 90% of either PTV receives the prescribed
dose, and an unacceptable deviation will be noted if < 90% of the PTV receives the
prescribed dose. The maximum dose in the PTVp (the PTVn is expected to have greater
heterogeneity and no specific constraints are given) above the prescribed dose will be 7%;
an acceptable variation will be > 7% to ≤ 12% and an unacceptable deviation >12%. The
planned dose between 64.8 to 70.2 will be declared after the patient is planned and all
dosimetric parameters finalized. A minimum of four treatment fields should be used.
The normal tissue outlines will be the same as described in Section 6.4.1.3, with the added
contouring of the potential space for small/large bowel in the pelvis. The potential bowel
space will include the space on either side of the bladder to the medial edge of the lymph
node outline laterally, beginning approximately at the top of the prostate bed field to one CT
axial imaging level above the most superior level displaying a CTVn contour. Care should be
taken to avoid the presacral lymph node region in the bowel volume. No constraints will be
placed on the bowel for 3D-CRT planning.
PLNRT Planning for IMRT (11/23/11)
The volumes, prescriptions and margins for the CTVns and PTVns will be the same as for
3D-CRT and IMRT. The recommended volumes are on the RTOG website under the “Core
Lab/Contouring Atlases” menu
(http://www.rtog.org/CoreLab/ContouringAtlases/ProstatePelvicLymphNodes.aspx).
No specific field arrangement is required, although typically 5-9 fields are used. Rotational
IMRT treatments are permitted, as long as the constraints are met (See Section 5.2). The
posterior PTVn margin at the bladder neck-rectum interface should not include the entire
width of the rectum. A composite plan should be generated showing that at least 95% of the
PTVn and PTVp receive the prescribed dose; a variation acceptable will be noted if < 95%
to 90% of the PTV(s) receives the prescribed dose, and a deviation unacceptable will be
noted if < 90% of the PTV(s) receives the prescribed dose. The maximum dose within the
PTVp (the PTVn is expected to have greater heterogeneity and no specific constraints are
given), above the prescribed dose, will be 15%; an acceptable variation will be > 15% to ≤
20% and an unacceptable deviation > 20%. The other dosimetric parameters for IMRT are
the same as for PBRT, except for the addition of a small bowel constraint.
16
RTOG 0534
Small/Large Bowel: The volume to be contoured is described in Section 6.4.3.1. For the
patients receiving PLNRT, ≤ 150 cc of potential bowel space should receive ≥ 45 Gy. A
variation will be noted if > 150 cc to 200 cc of potential small bowel space receives ≥ 45 Gy.
A secondary variation will be noted if >200 cc receives >45 Gy (see Section 6.5.6). Since
there are not protocol violations for bowel, treatment volumes should not be dramatically
altered to adjust for bowel. In prior protocols, considerable bowel was in the field and
patients tolerated treatment well. Thus, these constraints act as a guide.
Overlap of the Bowel with the Prostate Bed PTV: This situation has been one of concern in
cases where the high dose PTVp overlaps with loops of bowel. Since these patients have
had prior surgery, bowel is not as mobile as for the patient with an intact prostate. However,
it should be kept in mind that such compromises were not done in prior studies and that this
should be an infrequent occurrence.
Overlap of the Bowel with the Lymph Node PTV: No adjustments in the PTVn are permitted.
Since the potential bowel contour abuts the lymph node CTV, there should be an overlap
with the lymph node PTV(PTVn). The overlap is expected.
Use of cone beam CT and plan adjustment: There may be cases in which the target and
surrounding normal tissues are found to not be reproducible relative to the simulation CT
and consequent plan. It should be emphasized that replanning should be avoided if at all
possible because this will be considered a deviation. If the patient must be replanned in the
opinion of the treating physician, then a deviation will be recorded, but continue to treat the
patient per protocol in terms of dose and CTV/PTV volumes.
The following table summarizes the naming of targets and critical structures for submission
of data to RTOG.
Note: All required structures must be labeled as listed in the table below for digital RT data
submission. Resubmission of data may be required if labeling of structures does not
conform to the standard DICOM name listed.
RTOG 0534 Structure Names
Arms 1 and 2 Only
CTVp
PTVp
Bladder
BladdermCTV
Rectum
Femur_R
Femur_L
PenileBulb
SeminalVesicle
External
Arm 3 Only
CTVn
CTVp
PTVn
PTVp
Bladder
BladdermCTV
Rectum
Femur_R
Femur_L
PenileBulb
SmallBowel
SeminalVesicle
External
17
RTOG 0534
6.5
6.5.1
6.5.2
6.5.3
6.5.4
6.5.5
6.5.6
6.5.7
6.6
6.6.1
6.6.2
6.6.3
6.7
6.7.1
6.7.1.1
6.7.1.2
6.7.2
6.7.2.1
6.7.2.2
Critical Structures (12/10/13)
The critical normal structures are the bladder, rectum, small/large bowel above the rectum, and
femoral heads. The normal tissues will be contoured and considered as solid organs.
The bladder should be contoured from its base to the dome, excluding the CTVp (the CTVp
includes the bladder neck).
The rectum should be contoured from the anus (at the level of the ischial tuberosities) to the
rectosigmoid flexure (this is roughly at about 10 cm) or for a maximum length of 15 cm if the
sigmoid flexure if felt to be higher.
Each femoral head should be outlined down to the interface between the greater and lesser
trochanters. Each femoral head should be considered separately.
For the patients who will undergo PLNRT treatment in Arm 3 using 3D-CRT or IMRT, the
external iliac, obturator, internal iliac and common iliac vessels/lymph node regions should be
outlined inferiorly from where the external iliacs become the inguinal vessels and superiorly
from the level of the common iliacs at L5-S1. The presacral lymph nodes from L5-S1 to S3
should be included.
For the patients who will undergo PLNRT treatment in Arm 3 using 3D-CRT or IMRT, the
potential bowel space (not individual loops of bowel) where the small and large bowel may fall
should be outlined. The borders are the abdominal wall anteriorly, pelvic sidewalls laterally
(excluding the pelvic lymph node regions), superiorly to one cut above the last axial CT image
on which the lymph nodes are outlined and inferiorly from the level of the top of CTVp (outlining
around the sides of the bladder near the top of the bladder to encompass the bowel that may
fall into these regions). Posteriorly, the small bowel potential space should extend to in front of
the sacrum, abutting the anterior presacral nodal contours.
The tissue within the skin and outside all other critical normal structures and PTV’s is
designated as unspecified tissue. See the RTOG web site at http://www.rtog,org to view
examples of target and normal tissue contours.
Documentation Requirements (12/10/13)
The institution will archive treatment prescription and verification images for later review by the
study chair if requested. For conformal RT, at least one port film or pretreatment alignment film
per field along with the digital reconstructed radiographs (DRRs) from the treatment planning
program or, alternatively, a simulation verification radiograph shall be acquired and kept for
evaluation if requested except where geometrically impractical. For IMRT, at least one port film
from each orthogonal film along with the digital reconstructed radiographs (DRRs) from the
treatment planning program shall be acquired and kept for evaluation. Note: Images are
required to be taken but not submitted.
RTOG will display isodose distributions through the planning target volume to verify correct
digital submission and conversion.
RTOG will compare the submitted DVHs for the PTV, designated critical structures, and
unspecified tissues with DVHs calculated by RTOG.
Compliance Criteria (3D-CRT and IMRT) (11/23/11)
Dose Heterogeneity
3D-CRT
The maximum dose in the PTV above the prescribed dose will be 7%; an acceptable
variation will be > 7% to ≤ 12% and an unacceptable deviation > 12 (see section 6.4.1.2).
IMRT
The dose heterogeneity in IMRT treatment plans is greater than that for 3D-CRT. The
maximum dose within the PTV, above the prescribed dose, will be 15%; an acceptable
variation will be > 15% to ≤ 20% and an unacceptable deviation > 20%. Although, the
maximum dose allowable in the PTV(s) will be 15% above the prescribed dose, it is possible
in the vast majority of cases to achieve less than 15%.
Normal Tissue Deviations
3D-CRT
No specific constraints for 3D-CRT are included, but the dose-volume criteria described for
IMRT below should be used as a guide. The dose volume histograms for the bladder,
rectum, femoral heads, penile bulb, and small/large bowel (for Arm 3–PLNRT plans) should
be included and the marker dose volumes when relevant (BladdermCTV, rectum each
femoral head and small bowel) for IMRT should be recorded.
IMRT (11/23/11)
Less than or equal to 35% and 55% of the rectum should receive ≥ 65 Gy and ≥ 40 Gy,
respectively. Less than or equal to 50% and 70% of the bladder minus CTVp
18
RTOG 0534
6.8
6.8.1
6.8.2
6.9
6.9.1
6.9.2
6.11
7.0
(BladdermCTV) should receive ≥ 65 Gy and ≥ 40 Gy, respectively. The criteria for the
bladder are relaxed because the dosimetric relationship of volume exposed to the specified
marker doses is much less clear and the bladder neck is included in the CTVp. Less than or
equal to 10% of each femoral head should receive ≥ 50 Gy. A variation acceptable will be
noted if up to an additional 5.0% of either the femoral head receives > 50 Gy. For the
patients receiving PLNRT, ≤ 150 cc of potential small/large bowel space should receive ≥ 45
Gy. A primary variation will be noted if > 150 cc to 200 cc of potential small/large bowel
space receives ≥ 45 Gy. A secondary variation will be noted if > 200 cc of potential
small/large bowel space receives ≥ 45 Gy.
R.T. Quality Assurance Reviews (12/10/13)
3D-CRT and IMRT
RTQA will facilitate the review of CTV(s), PTV(s), and designated organs at risk. These reviews
will be ongoing and performed remotely. The final cases will be reviewed within 3 months after
this study has reached the target accrual or as soon as complete data for all cases enrolled
have been received, whichever occurs first.
Common Contouring Mistakes to Avoid
CTVp (prostate bed): Do not follow European or Australian/New Zealand guidelines. The
RTOG guidelines should be followed very closely. Do not exclude the posterior bladder from
the CTVp above the pubic symphysis (this is the Australian/New Zealand consensus, but not
ours). The entire bladder neck is in the contour below the pubic symphysis; do not compromise
this volume by excluding any bladder. The anterior border is the posterior aspect of the pubic
symphysis.
Pelvic Lymph Nodes: Do not leave out the presacral lymph nodes.
Femoral Heads: Do not just contour the heads. The contours should extend down to the
interface between the lesser and greater trochanters.
Penile Bulb: Needs to be contoured.
Bowel: Contour the space, not individual loops of bowel.
Radiation Adverse Events
All patients will be seen weekly by their radiation oncologist during radiation therapy. Any
observations regarding radiation reactions will be recorded and should include attention toward
the following potential side effects:
 Small bowel or rectal irritation manifesting as abdominal cramping, diarrhea, rectal
urgency, proctitis, or hematochezia;
 Bladder complications including urinary frequency/urgency, dysuria, hematuria, urinary
tract infection, and incontinence;
 Radiation dermatitis.
Clinical discretion may be exercised to treat side effects from radiation therapy as described in
Section 9.1. Examples of typical medications used in the management of rectal side effects,
such as diarrhea, include diphenoxylate or loperamide. Bladder or rectal spasms are usually
treated with anticholinergic agents or tolterodine. Bladder irritation may be managed with
phenazopyridine. Erectile dysfunction is often treated with medical management or mechanical
devices.
Radiation Adverse Event Reporting (1/8/09)
See Section 7.7 for Adverse Events and 7.8 for Adverse Event Reporting Guidelines.
DRUG THERAPY
Institutional participation in hormone therapy studies must be in accordance with the Medical
Oncology Quality Control guidelines stated in the RTOG Procedures Manual.
(11/23/11) Short term androgen deprivation (STAD) will be administered to patients randomized to
Arms 2 and 3. STAD will begin, from the start of LHRH agonist injection, within 6 weeks (+/- 2
weeks) after registration.
7.1
7.1.1
Treatment (11/23/11)
Dose definition
Short term androgen deprivation (STAD) will be administered to patients randomized to Arms 2
and 3, will begin from the start of LHRH agonist injection within 6 weeks after registration, and
will consist of total androgen deprivation, using a combination of antiandrogen and LHRH
agonist therapy for a total of 4-6 months. The antiandrogen will be either flutamide at 250 mg
p.o. TID or bicalutamide at 50 mg p.o. QD. Antiandrogen therapy should begin at approximately
19
RTOG 0534
7.1.2
7.1.3
7.2
7.2.1
7.2.2
7.2.3
7.2.4
7.2.5
7.3
7.3.1
7.3.2
the same time as LHRH agonist injection but may be started up to two weeks earlier (1-14 days
prior to LHRH agonist injection). The antiandrogen will be stopped on the last day of treatment
± 14 days, which should be approximately 4 months of antiandrogen therapy. LHRH agonist
injection will consist of analogs approved by the FDA (or by Health Canada for Canadian
institutions), e.g., leuprolide, goserelin, buserelin, or triptorelin and may be given in any
possible combination, such that the total LHRH treatment time is 4-6 months. For example,
LHRH agonist injection(s) may be given as a single 4-month injection, a 4-month injection and
one to two 1-month injection(s), two 3-month injections, one to three 1-month and a 3-month
injection (4-6 months total), four to six 1-month injections, or a 6-month injection.
Duration of treatment
As outlined above, STAD, when administered, will be for a duration of 4-6 months.
Antiandrogen therapy will be given for approximately 4 months (started within 1-14 days prior to
the LHRH agonist and ending the last day of radiotherapy ± 14 days); LHRH agonists will be
given for 4-6 months.
Calcium and Vitamin D supplementation
Patients who are randomized to receive androgen deprivation therapy are encouraged to take
calcium at 500-1200 mg/day and vitamin D at 400-800 IU/day during androgen deprivation
therapy; however, these supplements are not required.
Study Agents: LHRH Agonists (11/23/11)
Description
LHRH agonists are long-acting analogs of the native LHRH peptide and are effective at
reducing serum testosterone. Analogs approved by the FDA (or by Health Canada for
Canadian institutions) can be used in this study.
Administration
LHRH analogs are administered with a variety of techniques, including subcutaneous insertion
of a solid plug in the abdominal wall (Zoladex), intramuscular injection (Lupron, Trelstar) or
subcutaneous injection (Eligard).The manufacturer’s instructions should be followed.
Adverse Events
Consult the package insert for comprehensive adverse event information. Class-related toxicity
is generally a manifestation of the mechanism of action and due to low testosterone levels. In
the majority of patients testosterone levels increased above baseline during the first week,
declining thereafter to baseline levels or below by the end of the second week of treatment.
The most common side effect of LHRH analogs is vasomotor hot flashes; edema,
gynecomastia, bone pain, thrombosis, and gastrointestinal disturbances have occurred.
Potential exacerbations of signs and symptoms during the first few weeks of treatment is a
concern in patients with vertebral metastases and/or urinary obstruction or hematuria which, if
aggravated, may lead to neurological problems such as temporary weakness and/or
paresthesia of the lower limbs or worsening of urinary symptoms. Other side effects include
impotence and loss of libido, weight gain, depression, dizziness, loss of bone density, anemia,
increased thirst and urination, unusual taste in the mouth, skin redness or hives, pain at
injection site, muscle mass and strength loss, hair changes, penile length and testicular volume
loss, increased cholesterol, hypertension, diabetes exacerbation, emotional lability, nausea,
vomiting, and rarely allergic generalized rash and difficulty breathing.
Storage
LHRH analogs should be stored as directed by the commercial supplier.
Supply
Commercially available; Note: Buserelin is not commercially available in the United States. It is
commercially available for use in Canada and other countries outside of the United States.
Eulexin (flutamide)
Description
Flutamide is a substituted anilide. It is a fine, light, yellow powder, insoluble in water but soluble
in common organic solvents such as aromatic or halogenated hydrocarbons. Its concentration
in plasma can be determined by gas chromatography. Flutamide is a nonsteroidal antiandrogen
that is metabolized into a hydroxylated derivative, which effectively competes with the
hydrotestosterone for androgen receptor sites.
Administration
The drug is administered orally at a dose of 250 mg (two 125-mg capsules) three times a day
for a total daily dose of 750 mg. Flutamide will begin between two weeks to one day prior to
starting LHRH agonist injection and will continue throughout radiotherapy. Administration will
be suspended only if there is an apparent or suspected reaction to the drug. See Section 7.3.4.
20
RTOG 0534
7.3.3
7.3.4
7.3.5
7.3.6
7.4
7.4.1
7.4.2
7.4.3
7.4.4
7.4.5
Flutamide will be terminated on the last day of radiotherapy. During radiotherapy
interruptions, flutamide will be continued.
Adverse Events
Consult the package insert for comprehensive adverse event information. The reported side
effects of treatment include diarrhea and anemia. A high percentage of patients treated with
flutamide alone developed gynecomastia within 2 to 8 months. There have been postmarketing reports of hospitalization, and, rarely, death due to liver failure in patients taking
flutamide. Evidence of hepatic injury included elevated serum transaminase levels, jaundice,
hepatic encephalopathy, and death related to acute hepatic failure. The hepatic injury was
reversible after prompt discontinuation of therapy in some patients. Approximately half of the
reported cases occurred within the initial 3 months of treatment with flutamide. Other side
effects include impotence and loss of libido, fatigue, and rarely photosensitivity.
Dose Modifications
If gastrointestinal disturbances (cramps, diarrhea) occur prior to initiation of radiotherapy,
flutamide will be withheld until the side effects subside; the drug will then be reintroduced at a
dose of 250 mg/day and increased (at 3-day intervals) to 500 mg/day and then to 750 mg/day
as tolerated. If gastrointestinal disturbances occur after administration of radiotherapy, it might
be difficult to identify their cause. However, if severity of diarrhea exceeds the level commonly
observed during pelvic irradiation, the toxicity will be ascribed to flutamide and the drug will be
permanently discontinued. AST or ALT will be measured pretreatment, then about every other
month during oral antiandrogen therapy. If AST or ALT increases ≥ 2 x upper institutional limit
of normal, flutamide must be discontinued.
Storage
Flutamide should be stored at temperatures ranging from 20-30 °C and protected from
excessive moisture.
Supply
Commercially available
Casodex (bicalutamide)
Description
Bicalutamide is a nonsteroidal antiandrogen, which has no androgenic or progestational
properties. The chemical name is propanamide, N-[4-cyano-3(trifluoromethyl)phenyl]- 3- [(4fluorophenyl)sulphonyl]- 2- hydroxy- 2- methyl, (+,-). Bicalutamide is a racemic mixture with the
antiandrogen activity residing exclusively in the (-) or R-enantiomer. Bicalutamide has a long
half-life compatible with once-daily dosing. Bicalutamide is well tolerated and has good
response rates in phase II trials.
Administration
Bicalutamide is administered orally at a dose of one 50 mg tablet per day. Bicalutamide will be
started from two weeks to one day prior to LHRH administration and continued throughout
radiotherapy. Administration will be suspended only if there is an apparent or suspected
reaction to the drug. Bicalutamide will be terminated on the last day of radiotherapy.
During radiotherapy interruptions, bicalutamide will be continued.
Adverse Events
Consult the package insert for comprehensive toxicity information. In animal experiments, birth
defects (abnormal genitalia, hypospadias) were found in male offspring from female animals
dosed with bicalutamide during pregnancy. Although offspring from male animals dosed with
bicalutamide did not show any birth defects, patients enrolled in this trial are advised not to
cause pregnancy nor donate sperm while receiving protocol therapy or during the first 3 months
after cessation of therapy. The use of barrier contraceptives is advised. The most frequent
adverse events reported among subjects receiving bicalutamide therapy are breast tenderness,
breast swelling, and hot flashes. When bicalutamide 50 mg was given in combination with an
LHRH analog, the LHRH analog adverse event profile predominated with a high incidence of
hot flashes (53%) and relatively low incidences of gynecomastia (4.7%) and breast pain (3.2%).
Other side effects include impotence and loss of libido, fatigue, and rarely photosensitivity and
diarrhea.
Dose Modifications
Bicalutamide should be discontinued in instances of chemical liver toxicity. AST or ALT will be
measured pretreatment and then every other month during antiandrogen therapy. If the AST or
ALT rises ≥ 2 x the institutional upper limit of normal, bicalutamide must discontinued.
Storage
Bicalutamide should be stored in a dry place at room temperature between 68-77°F.
21
RTOG 0534
7.4.6
7.5
7.6
7.7
Supply
Commercially available
Criteria for Discontinuation of Protocol Treatment (1/8/09)
Protocol treatment may be discontinued for any of the following reasons:
 Progression of disease;
 Unacceptable adverse events at the discretion of the treating physician(s);
 A delay in protocol treatment > 8 weeks.
If protocol treatment is discontinued, follow up and data collection will continue as specified in the
protocol.
Modality Review
The Principal Investigator/Radiation Oncologist, Alan Pollack, MD, PhD and the Urology CoChair, Leonard G. Gomella, MD will perform a Hormone Delivery Quality Review by sampling of
patients who receive or are to receive hormone therapy in this trial. The goal of the review is to
evaluate protocol compliance. The review process is contingent on timely submission of
hormone therapy treatment data as specified in Section 12.1. The scoring mechanism is: Per
Protocol/Acceptable Variation, Not Per Protocol, and Not Evaluable. A report is sent to each
institution once per year to notify the institution about compliance for each case reviewed in that
year.
Adverse Events (4/29/14)
As of January 1, 2011, this study will utilize the Common Terminology Criteria for Adverse Events
(CTCAE) version 4 for grading of all adverse events reported via CTEP-AERS; all case report
forms will continue to use CTCAE version 3.0. A copy of the CTCAE version 4 can be
downloaded from the CTEP home page (http://ctep.cancer.gov). All appropriate treatment areas
should have access to a copy of the CTCAE version 4.
All adverse events (AEs) as defined in the table below (7.8) will be reported via the CTEP-AERS
(CTEP Adverse Event Reporting System) application accessed via the CTEP web site
(https://eapps-ctep.nci.nih.gov/ctepaers/pages/task?rand=1390853489613).
Serious adverse events (SAEs) as defined in the table below (7.8) will be reported via CTEPAERS.
7.7.1
In order to ensure consistent data capture, serious adverse events reported on CTEPAERS reports also must be reported on an RTOG case report form (CRF). In addition, sites
must submit CRFs in a timely manner after CTEP-AERS submissions.
Adverse Events (AEs)
Definition of an AE: Any untoward medical occurrence associated with the use of a drug in
humans, whether or not considered drug related. Therefore, an AE can be any unfavorable
and unintended sign (including an abnormal laboratory finding), symptom, or disease
temporally associated with the use of a medicinal (investigational) product, whether or not
considered related to the medicinal (investigational) product (attribution of unrelated, unlikely,
possible, probable, or definite). (International Conference on Harmonisation [ICH], E2A, E6).
[CTEP, NCI Guidelines: Adverse Event Reporting Requirements. February 29, 2012;
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm]
In the rare event when Internet connectivity is disrupted, a 24-hour notification must be made to
the RTOG Operations Office at 1-800-227-5463, ext. 4189, for instances when Internet fails.
Once internet connectivity is restored, an AE report submitted by phone must be entered
electronically into CTEP-AERS.
7.7.2
Serious Adverse Events (SAEs) — Serious adverse events (SAEs) that meet expedited
reporting criteria defined in the table in Section 7.8 will be reported via CTEP-AERS. SAEs that
require 24 hour CTEP-AERS notification are defined in the expedited reporting table in Section
7.8. Contact the CTEP-AERS Help Desk if assistance is required.
Definition of an SAE: Any adverse drug event (experience) occurring at any dose that results
in any of the following outcomes:
 Death;
 A life-threatening adverse drug experience;
22
RTOG 0534




Inpatient hospitalization or prolongation of existing hospitalization;
A persistent or significant disability/incapacity;
A congenital anomaly/birth defect;
Important medical events that may not result in death, be life threatening, or require
hospitalization may be considered an SAE, when, based upon medical judgment, they
may jeopardize the patient and may require medical or surgical intervention to prevent
one of the outcomes listed in the definition.
Due to the risk of intrauterine exposure of a fetus to potentially teratogenic agents, any
pregnancy, including a male patient’s impregnation of his partner, must be reported via CTEPAERS in an expedited manner.
7.7.3
Acute Myeloid Leukemia (AML) or Myelodysplastic Syndrome (MDS)
AML or MDS that is diagnosed as a secondary malignancy during or subsequent to treatment
in patients on NCI/CTEP-sponsored clinical trials must be reported via the CTEP-AERS system
within 30 days of AML/MDS diagnosis.
Secondary Malignancy
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g.,
treatment with investigational agent/intervention, radiation or chemotherapy). A secondary
malignancy is not considered a metastasis of the initial neoplasm.
CTEP requires all secondary malignancies that occur following treatment with an agent under
an NCI IND/IDE be reported via CTEP-AERS. Three options are available to describe the
event:
 Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia [AML])
 Myelodysplastic syndrome (MDS)
 Treatment-related secondary malignancy
Any malignancy possibly related to cancer treatment (including AML/MDS) should also be
reported via the routine reporting mechanisms outlined in each protocol.
7.8
Second Malignancy
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT a
metastasis from the initial malignancy). Second malignancies require ONLY routine reporting
via CDUS unless otherwise specified.
CTEP-AERS Expedited Reporting Requirements (4/29/14)
All serious adverse events that meet expedited reporting criteria defined in the reporting table
below will be reported via CTEP-AERS, the CTEP Adverse Event Reporting System, accessed
via the CTEP web site,
https://eapps-ctep.nci.nih.gov/ctepaers/pages/task?rand=1398715802346.
Submitting a report via CTEP-AERS serves as notification to RTOG and satisfies RTOG
requirements for expedited adverse event reporting.
CTEP-AERS provides a radiation therapy-only pathway for events experienced that involve
radiation therapy only. These events must be reported via the CTEP-AERS radiation therapy-only
pathway.
In the rare event when Internet connectivity is disrupted, a 24-hour notification must be made to
the RTOG Operations Office at 1-800-227-5463, ext. 4189, for instances when Internet fails.
Once internet connectivity is restored, an AE report submitted by phone must be entered
electronically into CTEP-AERS.
 CTEP-AERS-24 Hour Notification requires that an CTEP-AERS 24-hour notification is
electronically submitted within 24 hours of learning of the adverse event. Each CTEP-AERS
24-hour notification must be followed by a CTEP-AERS 5 Calendar Day Report. Serious
adverse events that require 24 hour CTEP-AERS notification are defined in the expedited
reporting table below.
23
RTOG 0534


Supporting source document is not mandatory. However, if the CTEP-AERS report indicates
in the Additional Information section that source documentation will be provided, then it is
expected. If supporting source documentation accompanies an CTEP-AERS report, include
the protocol number, patient ID number, and CTEP-AERS ticket number on each page, and
fax supporting documentation to the RTOG dedicated SAE FAX, 215-717-0990.
A serious adverse event that meets expedited reporting criteria outlined in the following table
but is assessed by the CTEP-AERS System as “expedited reporting NOT required” must still
be reported to fulfill RTOG safety reporting obligations. Sites must bypass the “NOT
Required” assessment; the CTEP-AERS System allows submission of all reports regardless
of the results of the assessment.
CTEP defines expedited AE reporting requirements for phase 2 and 3 trials as described in the
table below. Important: All AEs reported via CTEP-AERS also must be reported on the AE
section of the appropriate case report form (see Section 12.1).
Phase 2 and 3 Trials Utilizing Agents under a non-CTEP IND: CTP-AERS Expedited
Reporting Requirements for Adverse Events that Occur within 30 Days1 of the Last Dose
of the Commercially Available Agents in this Study (Arms 2 & 3)
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312)
NOTE: Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events,
whether or not they are considered related to the investigational agent(s)/intervention (21 CFR
312.64)
An adverse event is considered serious if it results in ANY of the following outcomes:
1) Death
2) A life-threatening adverse event
3) An adverse event that results in inpatient hospitalization or prolongation of existing
hospitalization for ≥ 24 hours
4) A persistent or significant incapacity or substantial disruption of the ability to conduct normal
life functions
5) A congenital anomaly/birth defect.
6) Important Medical Events (IME) that may not result in death, be life threatening, or require
hospitalization may be considered serious when, based upon medical judgment, they may
jeopardize the patient or subject and may require medical or surgical intervention to prevent
one of the outcomes listed in this definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6).
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI
via CTEP-AERS within the timeframes detailed in the table below.
Hospitalization
Resulting in
Hospitalization
≥ 24 hrs
Not resulting in
Hospitalization
≥ 24 hrs
Grade 1
Timeframes
Grade 2
Timeframes
Grade 4 & 5
Timeframes
Grade 3
Timeframes
10 Calendar Days
24-Hour 5 Calendar
Days
Not required
10 Calendar Days
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RTOG 0534
NOTE: Protocol specific exceptions to expedited reporting of serious adverse events are found in
the Specific Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR
Expedited AE reporting timelines are defined as:
o “24-Hour; 5 Calendar Days” - The AE must initially be reported via CTEP-AERS within 24
hours of learning of the AE, followed by a complete expedited report within 5 calendar days
of the initial 24-hour report.
o “10 Calendar Days” - A complete expedited report on the AE must be submitted within 10
calendar days of learning of the AE.
1
Serious adverse events that occur more than 30 days after the last administration of
investigational agent/intervention and have an attribution of possible, probable, or definite require
reporting as follows:
Expedited 24-hour notification followed by complete report within 5 calendar days for:

All Grade 4, and Grade 5 AEs
Expedited 10 calendar day reports for:
 Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization
 Grade 3 adverse events
2
For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive
half lives, rounded UP to the nearest whole day, after the agent/intervention was last
administered. Footnote “1” above applies after this reporting period.
Effective Date: May 5, 2011
Additional Instructions or Exceptions to CTEP-AERS Expedited Reporting Requirements
for Phase 2 and 3 Trials Utilizing an Agent under a non-CTEP-IND:
Not applicable to this study.
8.0
SURGERY
All patients must have undergone radical prostatectomy prior to being considered for enrollment in this
study. Any type of radical prostatectomy will be permitted, including retropubic, perineal, laparoscopic or
robotically assisted. If performed, the number of lymph nodes removed per side of the pelvis and the
extent of the pelvic lymph node dissection (obturator vs. extended lymph node dissection) should be
noted.
9.0
OTHER THERAPY
9.1
Permitted Supportive Therapy
All supportive therapy for optimal medical care will be given during the study period at the
discretion of the attending physician(s) within the parameters of the protocol and documented on
each site’s source documents as concomitant medication.
9.1.1
Antidiarrheals
Antidiarrheals, such as loperamide hydrochloride or diphenoxylate-atropine, may be used as
needed. The amounts of the drug(s) and dates used should be documented as much as
possible.
9.1.2
Antispasmatics
Antispasmatics, such as oxybutynin or tolterodine tartrate, may be used as needed. The
amounts of the drug(s) and dates used should be documented as much as possible.
9.1.3
Alpha Blockers
Alpha blockers, such as doxazosin mesylate, terazosin hydrochloride or tamsulosin
hydrochloride may be used as needed. The amounts of the drug(s) and dates used should be
documented as much as possible.
9.1.4
Analgesics
Analgesics is a broad category, including non-narcotic and narcotic agents. The use of nonnarcotic agents, such as acetaminophen, non-steroidal anti-inflammatory agents or
phenazopyridine hydrochloride for radiotherapy treatment-related pain should be documented
as much as possible. Narcotic use as a consequence of treatment should also be recorded.
25
RTOG 0534
9.1.5
9.2
10.0
Erectile Dysfunction
Erectile dysfunction may be treated with medical management (e.g., phosphodiesterase
inhibitors), vacuum pumps or other devices as appropriate. The amounts of the drug(s) used
and the dates that medical management or the use of mechanical devices was started should
be documented.
Treatment of Patients with Subsequent Disease Progression
Treatment of patients who have failed salvage radiotherapy therapy by criteria described in
Section 11 may receive additional medical or surgical therapies. The selection of these therapies
will be left to the discretion of the treating physician.
TISSUE/SPECIMEN SUBMISSION (2/13/08)
10.1
General Information
The RTOG Biospecimen Resource at the University of California San Francisco acquires and
maintains high quality specimens from RTOG trials. Tissue from each block is preserved through
careful block storage and processing. The RTOG encourages participants in protocol studies to
consent to the banking of their tissue. The RTOG Biospecimen Resource provides tissue
specimens to investigators for translational research studies. Translational research studies
integrate the newest research findings into current protocols to investigate important biologic
questions. The RTOG Biospecimen Resource also collects tissue for Central Review of
pathology.
In this study, tissue will be submitted to the RTOG Biospecimen Resource for the purpose of
central review of pathology (mandatory) and tissue banking for biomarker studies (highly
recommended but not required).
10.2
10.2.1
10.2.2
10.2.3
10.2.4
10.3
(3/31/09) Biomarker studies are being done on all RTOG prostatic cancer protocols using the
original diagnostic material. The emphasis has been on proliferation markers (e.g., DNA-ploidy,
Ki-67), apoptotic pathway markers (e.g., p53, MDM2, bcl-2, bax, p16), and angiogenesis markers
(e.g., COX-2, VEGF) [See Section 1.4]. These markers have shown promise in predicting
prostate cancer patient outcome after definitive radiotherapy. A final decision on which markers
will be studied awaits the results of completed RTOG prostate cancer trials that have reached
maturity (e.g., 86-10, 92-02, 94-13). The trial described here will not be ready for biomarker
analysis for several years, with the exception of the Abeta analysis in serum, which will be
conducted in conjunction with cognitive outcomes, for those who participate in the neurocognitive
battery testing. The goal is to measure approximately 5-10 biomarkers using the archived
pathologic material
Specimen Collection For Central Pathology Review: Required
The following material must be provided to the RTOG Biospecimen Resource for Central Review:
Representative H & E stained slides from the prostatectomy specimen that document the
Gleason score, extraprostatic extension, margin status, lymph node negativity or not assessed,
and seminal vesicle status must be submitted for central pathology review.
A Pathology Report documenting that the submitted tissue specimen contains tumor; the report
must include the RTOG protocol number and patient’s case number. The patient’s name and/or
other identifying information should be removed from the report. The surgical pathology
numbers and information must NOT be removed from the report.
A Specimen Transmittal Form stating that the tissue is being submitted for Central Review.
The Form must include the RTOG protocol number and the patient’s case number.
Central Review will be performed for every case by the Pathology Co-Chair, Mahul Amin, MD.
Specimen Collection for Tissue Banking for Biomarker Studies: Strongly recommended
(11/23/11)
For patients who have consented to participate in the tissue/blood/urine component of the
study (See Appendix I).
10.3.1
Sites may submit the following specimens:
10.3.1.1
(3/31/09) A paraffin-embedded tissue block of the tumor (preferred) or at least 10 unstained
5 micron sections on positively charged slides. If tumor heterogeneity is observed, the
submission of multiple blocks, including tissue from the area having the highest Gleason
score, is desirable. Note: Tissue block or slides must be clearly labeled with the pathology
identification number that corresponds to the Pathology Report.
26
RTOG 0534
10.3.1.2
10.3.1.3
The following must be provided in order for the case to be evaluable for the Biospecimen
Resource:
 A Pathology Report documenting that the submitted block contains tumor. The report
must include the RTOG protocol number and patient’s case number. The patient’s
name and/or other identifying information should be removed from the report. The
surgical pathology numbers and information must NOT be removed from the report.
 A Specimen Transmittal Form clearly stating that tissue is being submitted for the
RTOG Biospecimen Resource; if for translational research, this should be stated on the
form. The form must include the RTOG protocol number and patient’s case number.
Serum, plasma, whole blood, and urine
See Appendix V for the blood and urine collection kits and instructions. Note: Kits include a
label for shipping.
The following must be provided in order for the case to be evaluable for the Biospecimen
Resource: A Specimen Transmittal Form (STF) documenting the date of collection of the
serum, plasma, whole blood, and/or urine; the RTOG protocol number, the patient’s case
number, and method of storage, for example, stored at -80° C, must be included.
Specimen Collection Summary
Specimen Collection for Central Review/Tissue Banking
Specimens taken from
Collected when: Submitted as:
Shipped:
patient:
Representative H&E stained
slides of the primary tumor
A paraffin-embedded tissue
block or 10-15 unstained
slides on plus slides of the
primary tumor taken before
initiation of treatment
SERUM: 5-10 mL of whole
blood in 1 red-top tube and
centrifuge
PLASMA: 5-10 mL of
anticoagulated whole blood in
EDTA tube #1 (purple/
lavender top) and centrifuge
DNA: 5-10 mL of
anticoagulated whole blood in
EDTA tube #2 (purple/
lavender top) and mix
10-20 mL clean-catch urine
10.3.2
Pretreatment
H&E stained slide
Slide shipped ambient
Pretreatment
Block or unstained
slides
Block or unstained
slides shipped ambient
Pretreatment
Week 6 of RT
3, 6, 12 months (±1
month) after end of
RT; then yearly for
6 years (±2
months)
Pretreatment
Week 6 of RT
3, 6, 12 months (±1
month) after end of
RT; then yearly for
6 years (±2
months)
Pretreatment
Week 6 of RT
Frozen serum samples
containing 0.5 mL per
aliquot in 1 mL cryovials
(five to ten)
Serum sent frozen on
dry ice via overnight
carrier
Frozen plasma samples
containing
0.5 mL per aliquot in
1 mL cryovials (five to
ten)
Plasma sent frozen on
carrier
Frozen whole blood
samples containing
1 ml per aliquot in 1ml
cryovials (three to five)
Two 5-10 mL urine
aliquots in 2 sterile 15
ml polypropylene
centrifuge tubes.
Store frozen at
-20 or 80 C
Whole blood sent
frozen on dry ice via
overnight carrier
Pretreatment
Week 6 of RT
3, 6, 12 months (±1
month) after end of
RT; then yearly for
6 years (±2
months)
Urine sent frozen on
carrier
Storage Conditions (10/22/09)
Store at-80 C (-70C to -90C) until ready to ship. If a -80C Freezer is not available:
 Samples can be stored short term in a -20 C freezer (non-frost free preferred) for up to
one week (please ship out Monday-Wednesday only).
OR:
 Samples can be stored in plenty of dry ice for up to one week, replenishing daily (ship out
Monday-Wednesday only).
OR:
27
RTOG 0534
 Samples can be stored in liquid nitrogen vapor phase (ship out Monday-Wednesday only).
Please indicate on Specimen Transmittal Form the storage conditions used and time stored.
10.3.3
Submit materials for Central Review and Tissue Banking as follows:
U.S. Postal Service Mailing Address: For Non-frozen Specimens Only
RTOG Biospecimen Resource
University of California San Francisco
Campus Box 1800
2340 Sutter Street, Room S341
San Francisco, CA 94143-1800
Courier Address (FedEx, UPS, etc.): For Frozen Specimens
Questions: 415-476-RTOG (7864)/FAX 415-476-5271; [email protected]
10.4
Reimbursement (11/23/11)
RTOG will reimburse institutions for submission of protocol specified biospecimen materials sent
to the Biospecimen Resource at the University of California San Francisco and other protocolspecified collection repositories/laboratories. After confirmation from the RTOG Biospecimen
Resource or other designated repository/laboratory that appropriate materials have been
received, RTOG Clinical Trials Administration will authorize payment according to the schedule
posted with the Reimbursement and Case Credit Schedule found on the RTOG web site
(http://www.rtog.org/LinkClick.aspx?fileticket=Csxzt1v1hEk%3d&tabid=323). Biospecimen
payments will be processed quarterly and will appear on the institution’s summary report with the
institution’s regular case reimbursement.
10.5
Confidentiality/Storage (1/8/09)
(See the RTOG Patient Tissue Consent Frequently Asked Questions,
http://www.rtog.org/Researchers/BiospecimenResource/BiospecimenResourceFAQs.aspx for
further details.)
10.5.1
Upon receipt, the specimen is labeled with the RTOG protocol number and the patient’s case
number only. The RTOG Biospecimen Resource database only includes the following
information: the number of specimens received, the date the specimens were received,
documentation of material sent to a qualified investigator, type of material sent, and the date
the specimens were sent to the investigator. No clinical information is kept in the database.
10.5.2
Specimens for tissue banking will be stored for an indefinite period of time. Specimens for
central review will be retained until the study is terminated. If at any time the patient withdraws
consent to store and use specimens, the material will be returned to the institution that
submitted it.
11.0
PATIENT ASSESSMENTS
11.1
Study Parameters: See Appendix II for a summary of assessments and time frames.
11.2
Evaluation During Treatment (11/23/11)
Radiotherapy for Arm 1 begins within 6 weeks (+/- 2 weeks) after registration.
Radiotherapy for Arms 2 and 3 begins 2 months after the start of STAD (+/- 2 weeks).
11.2.1
Prior to radiotherapy
11.2.1.1
The AUA SI questionnaire should be administered to all patients prior to protocol treatment.
For patients on Arms 2 and 3, the AUA SI questionnaire should be administered within 2
weeks of starting RT.
11.2.1.2
For all patients, including those on androgen deprivation (Arms 2 and 3), the following lab
evaluations should be done within 30 days prior to starting treatment: CBC, AST or ALT,
PSA, and testosterone. For patients on Arms 2 and 3, these same labs should be drawn
within 2 weeks of starting RT.
11.2.1.3
(3/31/09) The QOL measures (EPIC, HSCL-25, EQ-5D, and Utilization of Sexual
Medications and/or Devices), the neurocognitive test battery (HVLT-R, Trail Making Test
Parts A & B, and COWAT), and serum for biomarkers, including Beta Amyloid, will be
28
RTOG 0534
obtained at pretreatment (baseline), if the patient has consented to participate in these
components of the study. Note: Participation in the neurocognitive test battery is optional for
the institution as well as the patient. Institutions participating in the neurocognitive test
battery must follow the certification process (See Section 11.9.5 and Appendix VI).
11.2.2
During radiotherapy
Patients will be seen and evaluated at least weekly during radiation therapy with documentation
of performance status and tolerance, including acute reactions.
11.2.2.1
During week 6 of RT, a CBC, AST or ALT, and testosterone should be obtained.
11.2.2.2
During week 6 of RT, the AUA SI questionnaire should be administered.
11.2.2.3
(3/31/09) The QOL measures (EPIC, HSCL-25, EQ-5D, and Utilization of Sexual
Medications and/or Devices), the neurocognitive test battery (HVLT-R, Trail Making Test
Parts A & B, and COWAT), and serum for Beta Amyloid also should be obtained during
week 6 of RT, if the patient has consented to participate in these components of the study.
Note: Participation in the neurocognitive test battery is optional for the institution as well as
the patient. Institutions participating in the neurocognitive test battery must follow the
certification process (See Section 11.9.5 and Appendix VI).
11.2.2.4
If the patient has consented to participate in the tissue/blood component of the study, blood
(serum, plasma, and whole blood) and urine will be collected during week 6 of RT.
11.3
Evaluation Following Radiotherapy (11/23/11)
11.3.1
At each follow-up visit (3, 6, and 12 months in year 1; q 6 months x 6 years, yearly thereafter
unless otherwise indicated; all visits are +/-1month for two years and then +/-2 months
thereafter), the patient will have an interval history, physical examination (including digital rectal
examination), assessment of specific GU and GI toxicity, and the AUA SI questionnaire will be
administered.
11.3.2
The following lab evaluations will be done:
11.3.2.1 PSA will be drawn at 1.5 months (+/-2 weeks), 3 months (+/-1 month), 6 months (+/-1 month), 9
months (+/-1 month) and 12 months (+/-1 month) after radiotherapy, at 3 month intervals (+/-1
month) for the next year. The type of PSA assay (e.g., Abbott) should be recorded on the data
forms.
11.3.2.2 If the PSA is ≤ 0.1 ng/mL, PSA will be drawn as described in section 11.3.2.1 and at 6-month
intervals thereafter (+/-2 months).
11.3.2.3 If the PSA is ≥ 0.2 ng/mL, then PSAs should be obtained at 3-month intervals (+/-1 month) until
the PSA is ≤ 0.1 ng/mL or greater than the nadir+2 ng/mL. If the PSA reverts to undetectable,
then the frequency of PSAs will revert to that described in sections 11.3.2.1 and 11.3.2.2.
Salvage therapy should not be initiated prior to the time at which the nadir+2 ng/mL
endpoint is reached.
11.3.2.4 If the PSA is ≥ 0.2 ng/mL, then follow-up visits should continue at 6-month intervals until the
PSA is greater than the nadir+2 ng/mL. Salvage therapy should not be initiated prior to the time
at which the nadir+2 ng/mL endpoint is reached.
11.3.2.5 Serum testosterone will be obtained with each PSA measurement.
11.3.2.6 AST or ALT will be obtained at 1.5 (+/-2 weeks), 3 (+/-1 month), and 6 months (+/-1 month)
after radiotherapy.
11.3.2.7 A CBC will be performed at 3 and 6 months (+/-1 month) after completion of RT.
11.3.3
The patient should be followed at 3-month intervals (+/-1 month) if ≥ grade 2 GI or GU
complications are present, unless these symptoms have been present for more than 6 months
and are not changing.
11.3.4
A bone scan and CT scan of the abdomen and pelvis will be performed as clinically indicated,
such as if the patient develops a PSA recurrence with a doubling time < 10 months or if the
patient develops symptoms suggesting the presence of metastatic disease.
11.3.5
If the patient has consented to participate in the tissue/blood component of the study, serum/
plasma, and urine for biomarkers (including for Beta Amyloid) should be obtained at 3, 6, and
12 months and then yearly for 6 years after completion of RT (see Section 10 and Appendix V).
11.3.6
(3/31/09) If the patient has consented to participate in the QOL and neurocognitive component
of the study, the QOL measures (EPIC, HSCL-25, EQ-5D, and Utilization of Sexual
Medications and/or Devices) should be obtained at 1 and 5 years post-RT (+/-2 months). The
neurocognitive test battery (HVLT-R, Trail Making Test Parts A & B, and the COWAT) should
be obtained at 1 and 5 years post-RT (+/-2 months). Note: Participation in the neurocognitive
test battery is optional for the institution as well as the patient. Institutions participating in the
neurocognitive test battery must follow the certification process (See Section 11.9.5 and
Appendix VI).
29
RTOG 0534
11.4
Criteria for Freedom from Progression (FFP)
The primary endpoint is FFP, which includes biochemical (PSA) failure, clinical failure, and
death from any cause.
11.4.1
Biochemical (PSA) Failure
The biochemical failure endpoint is defined according to the proposed new Radiation Therapy
Oncology Group/American Society for Therapeutic Radiology and Oncology (RTOG-ASTRO)
criteria (see section 1.3), also known as the Phoenix definition. The Phoenix definition is an
increase of the PSA level at least 2 ng/mL above the minimum level reached after therapy.43
Since the patients in this trial are status-post radical prostatectomy, about 70-80% will achieve
an undetectable PSA. In these cases, a PSA of 2 ng/mL is evidence of biochemical failure. All
PSA levels done during a follow-up interval will be recorded on the data forms. The initiation of
further “salvage” therapy in any form (e.g., androgen deprivation therapy, vaccine therapy, or
chemotherapy) after completion of protocol treatment and prior to nadir + 2 ng/mL failure will
not be counted as a failure and is strongly discouraged. The success of the trial depends
upon allowing the nadir + 2 ng/mL failure criteria to be met before any other therapeutic
intervention.
11.4.2
Clinical Failure
Clinical failure is defined as any evidence of local, regional or distant failure.
11.4.3
Time to FFP
Time to FFP will be measured from the date of randomization to the date of documented
biochemical failure by the Phoenix definition, clinical failure, or death from any cause.
11.5
Criteria for Local Failure
11.5.1
Local Failure
Local failure is defined as the development of a new palpable abnormality in the prostate bed
after enrollment in the protocol. The presence of a palpable abnormality in the prostate bed
prior to randomization is not permitted unless it is biopsy proven to be negative for cancer.
Needle biopsy is recommended for any new palpable abnormality. Patients who have a normal
exam and no evidence of biochemical failure by the primary endpoint will be considered
controlled locally. Patients with a new prostatic fossa abnormality and biochemical failure will
be considered to have local failure. Patients with a new prostatic fossa abnormality and no
evidence of biochemical failure should undergo prostatic fossa biopsy. If salvage therapy is
instituted prior to biopsy of a new prostatic fossa abnormality, then these patients will be
considered to have had local failure. The presence of palpable disease must be recorded on
the data collection forms for follow-up evaluations of the patient.
11.5.2
Biopsy of any new palpable abnormality in the prostatic fossa is recommended to document by
histologic criteria the presence of prostatic adenocarcinoma.
11.6
Criteria for Nonlocal Failure
11.6.1
Regional Metastasis
Regional metastasis will be documented if there is radiographic evidence (CT or MRI) of
lymphadenopathy (lymph node size ≥ 1.5 cm) in a patient without the diagnosis of a
hematologic/lymphomatous disorder associated with adenopathy. Histologic confirmation is not
required, although it is recommended in the setting of freedom from biochemical failure.
11.6.2
Distant Metastasis
Distant metastasis will be documented if by imaging (e.g., bone scan, CT, MRI) there is
evidence of hematogenous spread.
11.6.2.1
Time to Distant Failure
The time to distant failure will be measured from the date of randomization to the date of
documented distant disease.
11.7
Other Response Parameters
11.7.1
Secondary Biochemical Failure Endpoint
A more common biochemical endpoint used in the post-prostatectomy setting is a PSA ≥ 0.4
ng/mL and rising (see Section 1.3). This endpoint requires that the PSA is detectable and rising
for at least two values with the second value at 0.4 ng/mL or greater.
11.7.1.1
Time to Secondary Biochemical Failure
The time to a PSA of 0.4 ng/mL and rising will be calculated from the time of randomization
to this event, with a minimum follow-up from randomization of 2 years.
11.7.2
Hormone Refractory Disease
The development of hormone disease will be defined as three rises in PSA after the institution
of salvage hormone therapy.
11.7.2.1
Time to Hormone Refractory Disease
30
RTOG 0534
The time to hormone refractory disease will be calculated from the date of randomization to
the date of the third rise in PSA.
11.7.3
Cause-Specific Mortality
Time to cause-specific mortality will be measured from the date of randomization to the date of
death due to prostate cancer. Causes of death may require review by the study chair or their
designee. Death due to prostate cancer will be defined as:
11.7.3.1
Primary cause of death certified as due to prostate cancer or
11.7.3.2
Death in association with any of the following conditions:
 Further clinical or biochemical tumor progression occurring after initiation of "salvage"
anti-tumor (e.g., androgen deprivation) therapy;
 Three consecutive rises in the serum PSA level at > 3-month intervals that occur during
or after "salvage" androgen suppression therapy;
 Disease progression in the absence of any anti-tumor therapy;
 Death from a complication of therapy.
11.7.4
Overall Mortality
Time to overall mortality will be measured from the date of randomization to the date of death
from any cause. A post-mortem examination will be performed whenever possible and a copy
of the final post-mortem report will be sent to RTOG Headquarters.
11.8
Health-Related Quality of Life (HRQOL) (12/10/13)
Note: The Quality of Life component of this study closed to patient accrual on March 22, 2012. If
the patient provided consent to participate in the quality of life component of this study prior to
closure to new patient accrual, the site is required to administer the QOL assessments in follow
up as specified in Appendix II of the protocol.
11.8.1
Prostate Cancer-Specific Health-Related Quality of Life: EPIC
The Expanded Prostate Cancer Index Composite (EPIC) is a prostate cancer health-related
quality of life (HRQOL) patient self-administered instrument that measures a broad spectrum of
urinary, bowel, sexual, and hormonal symptoms related to radiotherapy and hormonal
therapy.57 Instrument development was based on advice from an expert panel and prostate
cancer patients, which led to expanding the 20-item University of California-Los Angeles
Prostate Cancer Index (UCLA-PCI) to the 50-item EPIC. Summary and subscale scores were
derived by content and factor analyses. Test-retest reliability and internal consistency were
high for EPIC urinary, bowel, sexual, and hormonal domain summary scores (each r ≥ 0.80 and
Cronbach's alpha ≥ 0.82) and for most domain-specific subscales. Correlations between
function and bother subscales within domains were high r > 0.60). Correlations between
different primary domains were consistently lower, indicating that these domains assess distinct
HRQOL components. EPIC domains had weak to modest correlations with the Medical
Outcomes Study 12-item Short-Form Health Survey (SF-12), indicating rationale for their
concurrent use. Moderate agreement was observed between EPIC domains relevant to the
Functional Assessment of Cancer Therapy Prostate module (FACT-P) and the American
Urological Association Symptom Index (AUA-SI), providing criterion validity without excessive
overlap.89 Utilization of Sexual Medications/Devices will be collected to provide a context for
interpreting the sexual domain score of the EPIC questionnaire.
11.8.2
EPIC is a robust prostate cancer HRQOL instrument that measures a broad spectrum of
symptoms; however, to decrease patient burden we will only use the domains most pertinent to
this study: urinary, bowel, sexual, and hormonal. The domains were validated separately, and
since each domain will be used intact, there is no threat to validity. Dutch and Japanese
translations of the EPIC are available, and a Spanish translation is planned but not yet
available. Sites can contact the Quality of Life/Outcomes Co-Chair, Dr. Bruner,
[email protected], to obtain translations.
Mood and Depression: HSCL-25
The 25-item version of the Hopkins Symptom Checklist (HSCL-25)90 will be used as a baseline
and follow-up measure of depressive symptoms.90-92 The patient self-administered measure is
closely related to the Brief Symptom Inventory93 and is widely used as a screening instrument
in the cancer patient population. Using a cutoff of 44 and above for caseness, Hough and
colleagues90 found that the HSCL-25 was comparable or superior to the Center for
Epidemiological Studies–Depression Scale in detecting psychiatric disorder. Note: If the
research nurse (or other person administering the QOL assessments) determines that a patient
scores 44 or greater on the HSCL-25, they should bring to the attention of the treating radiation
31
RTOG 0534
oncologist that the patient is possibly depressed. The treating physicians should evaluate the
patient and consider treatment or a referral to a psychiatrist.
11.9
The HSCL-25 has demonstrated reliability (Cronbach’s alpha >.90) and validity across a variety
of general and medical populations.94 Patients can complete the HSCL-25 in approximately 3-5
minutes. The HSCL-25 has been translated into Bosnian, Cambodian, Japanese, Laotian, and
Vietnamese. These translations can be ordered for a cost at http://www.hprtcambridge.org/Layer3.asp?page_id=10.
Neurocognitive Test Battery (12/10/13)
Note: The neurocognitive test battery component of this study closed to patient accrual on March
22, 2012. If the patient provided consent to participate in the neurocognitive test battery
component (a part of Quality of Life component) of this study prior to closure to new patient
accrual, the site is required to administer the neurocognitive assessments in follow up as
specified in Appendix II of the protocol.
The tests in the neurocognitive test cognitive battery were selected because they are widely-used
standardized psychometric instruments that have been shown to be sensitive to the neurotoxic
effects of cancer treatment in other clinical trials.95 The tests have published normative data that
takes into account age, and where appropriate, education and gender. All of the tests have been
translated into multiple languages. Sites can contact the Neuropsychology Co-Chair, Dr. Wefel,
[email protected], to obtain translations.
The tests are given by trained site administrators (see Section 11.9.5), and the total time for the
cognitive assessment is approximately 20 minutes, as follows:
Cognitive Domain
Memory
Verbal fluency
Cognitive Processing
Speed
Executive Function
11.9.1
11.9.2
11.9.3
11.9.4
11.9.5
Test
Hopkins Verbal Learning Test-Revised (HVLT-R)
Controlled Oral Word Association Test (COWAT)
Trail Making Test, Part A
Trail Making Test, Part B
Administration
Time (minutes)
5
5
2
5
Hopkins Verbal Learning Test-Revised (HVLT-R)96
The patient is asked to recall a list of 12 words in three semantic categories over three trials.
After a delay of at least 15 minutes, the patient is asked to recall the words. The patient is then
asked to identify the list words from distractors (both semantically related and unrelated). There
are six alternate forms of this test to minimize practice effects. The test measures learning
efficiency (total words recalled, Trials 1–3), delayed memory retrieval (delayed recall), and
consolidation (storage) of the information (delayed recognition). This measure has been widely
used in clinical trials.
Controlled Oral Word Association Test (COWAT)97
This is a test of phonemic verbal fluency. The patient is asked to produce as many words as
possible in 60 seconds beginning with a specified letter. There are two alternate forms of this
test.
Trail Making Test, Part A98
This is a measure of visual-motor cognitive processing speed, requiring the patient to connect
dots in numerical order from 1 to 25 as fast as possible.
Trail Making Test, Part B98
This is similar to Trail Making Test Part A, with the additional requirement of shifting mental set
(an executive function). The patient connects dots alternating numbers and letters as fast as
possible.
Quality Assurance for Neurocognitive Test Administration (1/17/12)
All persons administering the cognitive test battery must be certified. Previous certification for
RTOG 0212, RTOG 0214, RTOG 0424, or PCYC-0211A is not sufficient as the administration
of the HVLT-R has been changed. However, previous certification for RTOG 0525, 0614, or
0825 within the past 6 months will be accepted. Instructions for accessing the training video
and post-test are available from RTOG (see “Neurocognitive Training Procedure Letter” on the
RTOG website, www.rtog.org). Dr. Wefel, Neuropsychology Co-Chair and Chief ad interim of
Neuropsychology at M.D. Anderson Cancer Center, will oversee the training and will be
32
RTOG 0534
11.10
11.11
available to answer questions. Certification procedures and test instructions are provided in
Appendix VI. The instructions must be reviewed and retained for reference. Data forms are
available from RTOG. With training, administrators of the neurocognitive test battery should be
able to complete testing in approximately 20 minutes. Note: Participation in the neurocognitive
test battery is optional for the institution as well as the patient. Institutions participating in the
neurocognitive test battery must follow the certification process (See Appendix VI).
Beta-amyloid (Abeta) and Measures of Cognition and Mood and Depression (3/31/09)
As a correlative study, serum levels of beta-amyloid (Abeta) will be assessed at the same time
points as the HSCL-25, the HVLT-R, the COWAT, and the cognitive test battery; associations
among Abeta levels and cognitive tests will be evaluated. Beta-amyloid levels will be correlated
with testosterone levels to further elucidate the mechanism of any cognitive decline.
Note: Participation in the neurocognitive test battery is optional for the institution as well as the
patient. However, even if participation in the neurocognitive test battery is declined, blood
drawing for biosample collection and banking will continue as specified in Section 10.0 of the
protocol for patients that agree to participate in banking.
Cost Utility Analysis: EuroQol (EQ-5D)
The EQ-5D is a two-part patient self-administrated questionnaire that takes approximately 5
minutes to complete.99 The first part consists of 5 items covering 5 dimensions including: mobility,
self care, usual activities, pain/discomfort, and anxiety/depression. Each dimension can be
graded on 3 levels including: 1-no problems, 2-moderate problems, and 3-extreme problems.
Health states are defined by the combination of the leveled responses to the 5 dimensions,
generating 243 (35) health states to which unconsciousness and death are added.100 The second
part is a visual analogue scale (VAS) valuing current health state, measured on a 20-cm 10-point
interval scale. Worst imaginable health state is scored as 0 at the bottom of the scale, and best
imaginable health state is scored as 100 at the top. The Quality of Life/Outcomes Co-Chair, Dr.
Bruner, will review and specify the VAS score for each case.
Both the 5-item index score and the VAS score are transformed into a utility score between 0
“Worst health state” and 1 “Best health state.” The index score or the VAS score or the cost-utility
equation, can be used in the quality adjusted survival analysis depending on the health state(s) of
interest.101 For this study we will plan to report both the multidimensional and the VAS utilities for
comparative purposes between standardized HRQOL and current health state but will only use
the multidimensional utilities for the cost-utility analysis. The EQ-5D has now been translated into
most major languages, with the EuroQol Group closely monitoring the translation process;
translations can be accessed at http://www.euroquol.com.
12.0
DATA COLLECTION
Data should be submitted to:
RTOG Headquarters*
*If a data form is available for web entry, it must be submitted electronically.
Patients will be identified by initials only (first middle last); if there is no middle initial, a hyphen will be
used (first-last). Last names with apostrophes will be identified by the first letter of the last name.
12.1
Summary of Data Submission (12/10/13)
Due
Within 2 weeks of study entry
Item
Demographic Form (A5)
Initial Evaluation Form (I1)
Pathology Report (P1)
Slides/Blocks (P2)
American Urological Association Symptom Index
(AUA SI) (PQ)
HRQOL:
33
RTOG 0534
EPIC (FA);
HSCL-25 (HP);
EQ-5D (QF)
Utilization of Sexual Meds/Devices (SA)
Neurocognitive Evaluation Summary Form (CS):
HVLT-R;
Trail Making Test, Parts A & B;
COWAT
Interim Follow-up Form (F0)
Arms 2 and 3 only: Prior to RT start, 3 months
after RT (includes report of androgen suppression
treatment)
Follow-up Form (F1)
Arm 1: 3, 6, and 12 months after RT; then every 6
months x 6 years; then annually
Arms 2 and 3: 6 and 12 months after RT, then
every 6 months x 6 years; then annually
(AUA SI) (PQ)
Arm 1: During week 6 of RT; 3, 6, and 12 months
after RT; then every 6 months x 6 years; then
annually
Arms 2 and 3: 2 weeks prior to RT start; during
week 6 of RT; 3, 6, and 12 months after RT; then
every 6 months x 6 years; then annually
Neurocognitive Evaluation Summary Form (CS):
HVLT-R;
Trail Making Test, Parts A & B;
COWAT
During week 6 of RT, 1 year and 5 years post-RT
HRQOL:
EPIC (FA);
HSCL-25 (HP);
EQ-5D (QF)
Utilization of Sexual Meds/Devices (SA)
During week 6 of RT, 1 year and 5 years post-RT
Autopsy Report (D3)
As applicable
12.2
Summary of Dosimetry Digital Data Submission for 3D-CRT or IMRT (Submit to TRIAD; see
Section 5 for account access and installation instructions) [12/10/13]
Within 1 week of
start of RT
Preliminary Dosimetry Information
Digital data submission includes the following:

CT dataset with contours for all critical normal structures, CTV, and PTVs

Digital beam geometry for initial and boost beam sets

Doses for initial, boost and composite sets of concurrently treated beams

Digital DVH data for all required critical normal structures, CTV, and PTVs
for total dose plan
34
RTOG 0534

All required structures MUST be labeled per the table in Section 6.4

Digital Data Submission Information Form (DDSI)
Upon submission of the digital data via TRIAD, complete an online Digital
Data Submission Information Form (DDSI) (Form located on ATC web site,
http://atc.wustl.edu/forms/DDSI/ddsi.html)
Note: All simulation and portal films and/or digital film images will be kept by the
institution and ONLY submitted if requested.
Final Dosimetry Information
Radiotherapy Form (T1) [copy to HQ]
Daily Treatment Record (T5) [copy to HQ]
Within 1 week of
RT end
Note: Copies of simulation and port films/images will be submitted to RTOG
Headquarters ONLY if specifically requested.
13.0
STATISTICAL CONSIDERATIONS
13.1
Study Endpoints (11/23/11)
13.1.1
Primary Endpoint
Freedom from progression (FFP): FFP (Section 11.4), will be the first occurrence of
biochemical failure by the Phoenix definition (PSA ≥ 2 ng/ml over the nadir PSA),43 clinical
failure (local, regional or distant), or death from any cause.
13.1.2
Secondary Endpoints
13.1.2.1
Secondary biochemical failure: See Section 11.7.1;
13.1.2.2
Hormone-refractory disease: See Section 11.7.2;
13.1.2.3
Local Failure: See Section 11.5.1;
13.1.2.4
Distant metastasis: See section 11.6.2;
13.1.2.5
Cause-specific mortality: See Section 11.7.3;
13.1.2.6
Overall mortality: See Section 11.7.4;
13.1.2.7
Incidence of “acute” adverse events (based on CTCAE, v. 3.0.): The acute adverse events
will be the first occurrence of worst severity of the adverse event ≤ 90 days of the completion
of RT.
13.1.2.8
Time to “late” grade 2+ and 3+ adverse events (based on CTCAE, v. 3.0.): The time of a first
late grade 2+ or 3+ adverse event, defined as > 90 days from the completion of RT.
13.1.2.9
Comparison of disease-specific health related quality of life (HRQOL) change by EPIC,
HVLT-R, Trail Making Test, parts A & B, and COWAT;
13.1.2.10
Assessment of mood and depression change using QOL measured by the HSCL-25;
13.1.2.11
Assessment and comparison of Quality Adjusted Life Year (QALY) and Quality Adjusted
FFP Year (QAFFPY);
13.1.2.12
Evaluation and comparison of the cost-utility using EQ-5D;
13.1.2.13
Association between serum levels of beta-amyloid (Abeta) and measures of HSCL-25, the
HVLT-R, Trail Making Test, parts A & B, or the COWAT.
13.1.2.14
Prognostic value of genomic and proteomic markers for the primary and secondary clinical
endpoints.
13.1.2.15
To collect paraffin-embedded tissue blocks, serum, plasma, urine, and whole blood for
future translational research analyses.
13.1.2.16
To assess the relationship(s) between the American Urological Association Symptom Index
(AUA SI) and urinary morbidity (Adverse Event terms: Urinary frequency/urgency) using the
CTCAE v. 3.0 grading system.
13.2
Sample Size
13.2.1
Stratification and Randomization (1/8/09) (3/24/10)
Patients will be stratified before randomization according to seminal vesicle involvement (No
vs. Yes); prostatectomy Gleason score (≤ 7 vs. 8-9); pre-radiotherapy PSA (≥ 0.1 and ≤ 1.0
ng/ml vs. >1.0 and <2.0 ng/ml), and pathology stage (pT2 and margin negative vs. all others).
The treatment allocation scheme described by Zelen102 will be used because it balances
35
RTOG 0534
13.2.2
patient factors other than institution. Patients will be randomized to PBRT alone (Arm 1),
PBRT+NC-STAD (Arm 2), or PLNRT+PBRT+NC-STAD (Arm 3). The patients are randomized
to one of three arms until a treatment effect is detected or the total information time is reached.
If a decision is made regarding treatment effect during the accrual, patients will be randomized
as specified in Section 13.5.7.
Sample Size Derivation
The sample size calculation is based on the primary endpoint FFP rate by 5 years and the
assumption that patients are randomized to all three arms until the end of accrual. Based on
35-36
we project that the rate of 5-year
the prior results from a multi-institutional pooled analysis
FFP of Arm 1, p1 is 70% and hypothesize a 10% improvement in patients treated in Arm 2,
i.e., p2=80%, and a 20% improvement in patients treated in Arm 3, i.e., p3=90%. The sample
103
size calculation is based on the backward elimination decision rule in Chen and Simon
because this approach has the least favorable configuration property. We assume that the
three treatment arms are ranked with Arm 1 as the least favorable arm, Arm 2 as the second
one, and Arm 3 as the most favorable arm (p1 > p2 > p3). We define the probability of
selecting Arm i under hypothesis i (i=1, 2, 3) as P (D=i | Hi) = 1- αi. The three hypotheses are
as follows:
where, P (D=1 | H1) = 1- α1
H1: p1 = p2 = p3
where, P (D=2 | H2) = 1- α2
H2: p1 + δσ = p2 = p3
where, P (D=3 | H3) = 1- α3
H3: p1 + δσ = p2 + δσ = p3
Assume that the rates for all three arms are independently approximately normally distributed
2
and have the same variance σ /n= 0.25/n. We wish to detect a difference of 10% (δ*σ = δ*0.5
103
= 0.1). Assume that α1 =0.025, α2 =α3=0.15, and ζ=3.25 (from Table 4 in Chen and Simon ),
2
2
2
2
the sample size for each treatment arm, n=2*ζ / δ = 2*3.25 / 0.2 = 529 patients are needed to
have a statistical power of 90.1%.
13.3
Three interim analyses and a final analysis are planned for early stopping for efficacy and
futility. For efficacy, testing will be done at the significance level of 0.001, which is similar to the
104,105
106
and the futility testing is based on the Freidlin and Korn
method.
Haybittle-Peto test
Guarding against an ineligibility or lack-of-data rate of up to 10%, the final targeted accrual for
this study will be 1764 (588 per arm) patients.
Patient Accrual (11/23/11)
The proposed trial, RTOG 0534, builds on the experience obtained in RTOG 96-01. RTOG 9601 involved a similar group of patients treated postoperatively with salvage radiotherapy and
accrued 840 patients over 5 years at an average rate of 14 cases per month. As described
above, we anticipate at the minimum a similar accrual rate; however, what is notable about the
accrual in RTOG 96-01 is that at the end of the trial over 30 patients were being entered per
month. There was an extended ramp-up period in RTOG 96-01; it took 2.5 years for accrual in
RTOG 96-01 to reach 20 patients per month, and the trial reached targeted accrual and closed in
less than five years. We anticipate that accrual to RTOG 0534 will be faster during the ramp-up
period because the group has experience in accruing postoperative patients to randomized trials.
Moreover, in RTOG 0534, androgen deprivation therapy is only used for 4 months, whereas in
RTOG 96-01, it was used for 2 years. Many men are reluctant to take prolonged androgen
deprivation, and for this reason accrual to the new study might be more robust. We are
conservatively estimating an average of 16 cases per month in the new trial. We expect to
complete accrual in 9.2 years. Based on patient accrual in previous RTOG randomized prostate
studies, there will be relatively few entries during the initial 6 months while institutions are
obtaining IRB approval. The total duration of the study is expected to be 15 (14.7) years from the
time the first patient is entered to the final analysis with 5 years of follow-up for each patient, and
a uniform accrual rate of 16 patients per month.
The RTOG Data Monitoring Committee (DMC) will begin evaluating patient accrual semi-annually
following the anticipated quiet period. In accordance with CTEP policies for slowly accruing trials,
if the average monthly accrual rate for the trial in the fifth and sixth quarters after study activation
(i.e., in months 13-18) is less than 20% of the rate projected in the paragraph above (i.e., less
than 4 patients per month), the study will close to further accrual. If the average monthly accrual
rate is greater than 20% but less than 50% of projected (i.e., less than 8 patients per month), the
trial will be placed on probation for six months. If the average monthly accrual rate at the end of
36
RTOG 0534
the probationary period is less than 50% of projected, the study will close to future accrual. The
participation of non-RTOG institutions through CTSU is expected to follow a similar pattern as
seen in RTOG.
13.4
Power Calculations for Selected Secondary Endpoints
13.4.1
Secondary Biochemical Failure
The prior results from a multi-institutional pooled analysis35-36 show that Arm 1 has a 59% rate
of 5-year freedom from biochemical failure, and we project Arm 2 will have a 5-year freedom
from biochemical failure rate of 69%, and Arm 3 will have a 7-year freedom from biochemical
failure rate of 79%. With 529 analyzable patients per arm, we would have at least 87%
statistical power of detecting at least a 10% absolute improvement in the biochemical failure
rate in Arm 2 by 5 years compared to Arm 1 using a Z-test for the difference between the two
rates with the standard errors estimated by Greenwood’s method at the 0.0125 significance
level. Also, with 529 analyzable patients per arm, we would have at least 93% statistical power
of detecting at least a 10% absolute reduction in the biochemical failure rate in Arm 3 at 5 years
compared to Arm 2 using a Z-test for the difference between the two rates with the standard
errors estimated by Greenwood’s method at the 0.0125 significance level.
13.4.2
Overall Mortality (1/8/09)
The prior results from a multi-institutional pooled analysis36 show that Arm 1 has an 85% rate of
10 year overall survival, which translates to a yearly hazard rate of 0.0163. Based on this
result, we project Arm 2 will have a 10-year overall survival rate of 90%, which translates to a
yearly hazard rate of 0.0105, and Arm 3 will have a 10-year overall survival rate of 95%, which
translates to a yearly hazard rate of 0.0051. With 529 analyzable patients per arm, we would
have at least 47% statistical power of detecting at least a 6% (or a hazard rate of 0.648)
relative reduction in the yearly overall survival rate using a one-sided log-rank test at the
0.0125 significance level for patients in Arm 2. Also, with 496 analyzable patients per arm, we
would have at least 46% statistical power of detecting at least a 6% (or a hazard rate of 0.487)
relative reduction in the yearly overall survival rate using a one-sided log-rank test at the
0.0125 significance level for patients in Arm 3 compared to Arm 2.
13.4.3
Genomic and Proteomic Biomarkers (1/8/09)
Genomic or proteomic biomarkers will be categorized into either overexpressed or
underexpressed. At a minimum, the analyses will include DNA-ploidy, Ki-67, p53, MDM2, bcl-2,
bax, p16 and Cox-2. These biomarkers have shown promise in complementing the standard
clinical parameters of PSA, Gleason score, and stage in prior analyses of men treated primarily
for prostate cancer with RT. While these markers have been selected based on prior analyses,
it is likely that some other markers and/or methods will be investigated when the proposed trial
matures. Group 1 denotes a group with a better survival rate and Group 0 denotes the adverse
group with the overexpressed or underexpressed marker. Tests will be performed to determine
whether there is a difference in the survival functions for the primary endpoint, secondary
biochemical failure, hormone refractory disease, distant metastasis, cause-specific survival,
and overall survival. The number of events needed to obtain 1-β statistical power under these
assumptions is calculated based on Schoenfeld.107 In treatment efficacy trials, the targeted
hazard ratios are usually not that large and the Schoenfeld formula works well.
Nd = (z + z)2/[(log())2P0P1]
Where Pi = the proportion of patients allocated to group I. i=0,1
Λ = λ0/ λ1 (>1)
nd = The number of events (failure)
Zu=the uth percentile of the standard normal distribution
37
RTOG 0534
Tables 2 through 9 show the number of events for each biomarker required to demonstrate the
hazard ratio Λ at a significance level α = 0.025 with statistical power of 80% and 90%. P0 or P1
values for each biomarker are based on the previous studies.
Table 2: Number of events for Ki-67: P0 or P1=46%
HAZARD RATIO ( Λ)
STATISTICAL POWER
1.5
1.75
2
90%
258
136
89
80%
193
101
66
38
RTOG 0534
Table 3: Number of events for p53: P0 or P1=22%
HAZARD RATIO ( Λ)
STATISTICAL POWER
1.5
1.75
2
90%
373
196
128
80%
279
147
96
Table 4: Number of events for MDM2: P0 or P1=50%
HAZARD RATIO ( Λ)
STATISTICAL POWER
1.5
1.75
2
90%
256
135
88
80%
191
101
66
(ZΒ)
Table 5: Number of events for Bcl-2: P0 or P1=20%
HAZARD RATIO ( Λ)
STATISTICAL POWER
1.5
1.75
2
90%
400
210
137
80%
299
157
103
(ZΒ)
Table 6: Number of events for Bax: P0 or P1=47%
HAZARD RATIO ( Λ)
STATISTICAL POWER
1.5
1.75
2
90%
257
135
88
80%
192
101
66
(ZΒ)
39
RTOG 0534
Table 7: Number of events for Cox-2: P0 or P1=50%
HAZARD RATIO ( Λ)
STATISTICAL POWER
1.5
1.75
2
90%
256
135
88
80%
191
101
66
(ZΒ)
Table 8: Number of events for DNA-ploidy: P0 or P1=40%
HAZARD RATIO ( Λ)
STATISTICAL POWER
1.5
1.75
2
90%
267
140
92
80%
199
105
69
(ZΒ)
Table 9: Number of events for p16: P0 or P1= 27%
HAZARD RATIO ( Λ)
STATISTICAL POWER
(ZΒ)
1.5
1.75
2
90%
325
171
111
80%
243
128
83
13.5
Analysis Plan
All eligible patients who are randomized to the study will be included in the comparison of
treatment arms (intent-to-treat analysis).
13.5.1
Analysis of the Primary Endpoint (1/8/09)
FFP failure will be the first occurrence of local failure, regional failure, distant metastasis,
biochemical failure defined by the Phoenix definition (PSA ≥ 2 ng/ml + nadir PSA), or death
from any cause. Patients who are event free with less than 5 years of follow-up or who receive
any secondary salvage therapy (e.g., salvage androgen deprivation, vaccine therapy,
biologic/small molecule therapy, or chemotherapy) will be censored. The primary endpoint FFP
rate by 5 years is defined as the proportion of patients with a FFP failure by 5 years from the
randomization among all eligible patients at baseline and will be estimated by the Kaplan-Meier
method. The Z-test statistic for the difference between the two rates with the standard errors
estimated by Greenwood’s method will be used with an overall significance level of 0.025. The
following test statistics will be used for testing between Arm i and Arm j.
Tij 


pi  p j
n
ni
j
fj
fi
2
pˆ 
 pˆ j 
i 1 ri ( ri  f i )
i 1 r j ( r j  f j )
2
i
40
where, i,j =1,2,3
RTOG 0534
eq (1)

where, pi is FFP rate of Arm i estimated by Kaplan-Meier method, ri is the number of patients
who are at risk and fi is the number of patients who have FFP events. Using the backward
elimination decision procedure, we will first compare Arm 3 with Arm 2 at a critical value (Z-score)
of 1.6249. The following hypotheses are of interest to be tested, where, p1, p2, and p3 are the rate
of 5-year FFP of Arm 1, Arm 2 and Arm 3, respectively.
H01: p3 ≤ p2 vs. HA1: p3 > p2
If Arm 3 is not better than Arm 2 (p3 ≤ p2), then we compare Arm 2 with Arm 1. If Arm 3 is better
than Arm 2 (p3 > p2), then we compare Arm 3 with Arm 1.
If H01 is rejected (T23 > 1.6249), then we conclude that Arm 3 is better than Arm 2 and the
following hypotheses are tested.
H02: p3 ≤ p1 vs. HA2: p3 > p1
If the H02 is rejected (T13 > 2.0768), then we conclude that the 5-year FFP of Arm 3 will be better
than Arm 1. If the H02 is not rejected (T13 ≤ 2.0768), then we conclude that the 5-year FFP of Arm
3 will not be better than Arm 1.
If H01 is not rejected (T23 ≤ 1.6249), then we conclude that Arm 3 is not better than Arm 2 and the
H02: p2≤ p1 vs. HA2: p2 > p1
If the H02 is rejected (T12 > 2.0768), then we conclude that the 5-year FFP of Arm 2 will be better
than Arm 1. If the H02 is not rejected (T12 ≤ 2.0768), then we conclude that the 5-year FFP of
Arm 2 will not be better than Arm 2.
13.5.2
In addition, univariate and multivariate logistic regression108 will be used to compare the
treatment differences in each hypothesis. Odds ratios from univariate and multivariate logistic
regression and the respective 97.5% confidence intervals will be computed. Treatment arm, SV
involvement, prostatectomy Gleason score, pre-radiotherapy PSA, pathology stage, age, and
race (as appropriate) will be adjusted for in the Multivariate analysis.
Biochemical Failure-Related Endpoints (1/8/09)
The secondary biochemical failure (BF) endpoint is defined as having a detectable PSA (PSA
≥ 0.1 ng/ml) and rising for at least two values with the second value at 0.4 ng/ml or greater, or
the initiation of salvage therapy. Hormone refractory disease is defined as three rises in PSA
after the institution of second salvage hormone therapy. The rate pi (i=1, 2, 3) is defined as the
proportion of patients with an event among all eligible patients at baseline in Arm i. The Z-test
statistics for the difference between the two rates with the standard errors estimated by
Greenwood’s method, eq. (1), will be used with an overall significance level of 0.025. In the test

statistics, pi is the rate of Arm i estimated by Kaplan-Meier method, ri is the number of patients
who are at risk and fi is the number of patients who have events by 5 years. Using the
backward elimination decision procedure, we first compare Arm 3 with Arm 2. The following
hypotheses are of interest to be tested, where, p1, p2, and p3 are the rate of 5-year of Arm 1,
Arm 2 and Arm 3, respectively.
H01: p3 ≤ p2 vs. HA1: p3 > p2
If Arm 3 is not better than Arm 2 (p3 ≤ p2), then we compare Arm 2 with Arm 1. If Arm 3 is better
than Arm 2 (p3 > p2), then compare Arm 3 with Arm 1.
If H01 is rejected (T23 > 1.6249), then we conclude that Arm 3 is better than Arm 2 and the
H02: p3 ≤ p1 vs. HA2: p3 > p1
If the H02 is rejected (T13 > 2.0768), then we conclude that the 5-year rate of Arm 3 will be
better than Arm 1. If the H02 is not rejected (T13 ≤ 2.0768), then we conclude that the 5-year
rate of Arm 3 will not be better than Arm 1.
If H01 is not rejected (T23 ≤ 1.6249), then we conclude that Arm 3 is not better than Arm 2 and
the following hypotheses are tested.
H02: p2≤ p1 vs. HA2: p2 > p1
If the H02 is rejected (T12 > 2.0768), then we conclude that the 5-year rate of Arm 2 will be
better than Arm 1. If the H02 is not rejected (T12 ≤ 2.0768), then we conclude that the 5-year
rate of Arm 2 will not be better than Arm 2.
In addition, the univariate and multivariate logistic regression will be used to compare the
treatment differences in each hypothesis. Odds ratios from the univariate and multivariate
41
RTOG 0534
13.5.3
13.5.4
logistic regression and the respective 97.5% confidence interval will be computed. The
treatment arm, SV involvement, prostatectomy Gleason score, pre-radiotherapy PSA,
pathology staging, age, and race (as appropriate) will be adjusted for in the multivariate
analysis.
Time to Failure of Secondary Survival Endpoints (1/8/09)
The time to failure for secondary endpoints (second biochemical failure, hormone refractory
disease, distant metastasis, cause-specific mortality, and overall mortality) will be measured
from the date of randomization to the date of the event of interest. The events for secondary
endpoints and time-to-events are defined in Sections 11.4-11.7. Using the backward
elimination decision procedure, we will first compare Arm 3 with Arm 2 at the significance level
of 0.0125. If Arm 3 is not better than Arm 2, then Arm 2 will be compared with Arm 1 at the
significance level of 0.0125. If we conclude that Arm 2 will be better than Arm 1, then we can
conclude that the 5-year FFP of Arm 2 will be the best. If Arm 3 is better than Arm 2, then Arm
3 will be compared with Arm 1 at the significance level of 0.0125. If we conclude that Arm 3 will
be better than Arm 1, then we can conclude that Arm 3 will be the best. The time-to-event
distribution of overall mortality will be estimated using the Kaplan-Meier method109 and the logrank test110-111 will be used to test whether the overall mortality rate in one arm is higher than
the other arm for each hypothesis at the significance level of 0.0125. However, the treatment
effect on other types of failure may impact the observable measures of distant metastasis and
cause-specific mortality and other competing risks may dilute the sensitivity of hormone
refractory disease, distant metastasis and cause-specific mortality.106 We will use the causespecific hazard rate112-113 (the instantaneous rate of cause-specific mortality in the presence of
competing failure types as a function of time) approach to consider the competing events.
Freidlin and Korn106 showed that the cause-specific hazard rate approach is better than other
approaches, for example, the cumulative incidence method,114in most cases. The log-rank test
on the times to the specific type of failure, which considers the presence of competing events,
will be used to test whether the survival rates of these secondary endpoints in one arm are
higher than that of the other arm for each hypothesis at a significance level of 0.0125. In this
approach, patients who experience other failure first are censored.112
In addition, the Cox regression model115 will be used to compare the treatment differences.
Both unadjusted and adjusted hazard ratios and the respective 97.5% confidence interval will
be computed. At least the treatment arm, the stratification variables (SV involvement,
prostatectomy Gleason score, pre-radiotherapy PSA, pathology stage), age, and race (as
appropriate) will be adjusted for in this analysis.
Comparison of the Incidence of Acute Toxicity and Time to Late Grade 3+ Toxicity (1/8/09)
Adverse events are scored according to CTCAE, v. 3.0. An acute adverse event will be
defined as the worst severity of the adverse event occurring less than or equal to 90 days of
treatment. Both acute grade 2+ and 3+ toxicity will be examined separately. Univariate logistic
regression107 will be used to model the distribution of acute adverse events. Multivariate logistic
regression107 will be used to model the distribution of acute adverse events, adjusting for
covariates. Treatment arm, SV involvement, prostatectomy Gleason score, pre-radiotherapy
PSA, pathology stage, and age (as appropriate) will be adjusted for in the multivariate analysis.
Both unadjusted and adjusted odds ratios (H1: Arm 1 vs. Arm 2 and H2: Arm 2 vs. Arm 3,
respectively) and the respective 97.5% confidence interval will be computed and tested using a
one-sided chi-square test with the significance level of 0.025 for each hypothesis.
Late grade 2+ or 3+ adverse events will be defined as an a grade 2+ or 3+ adverse events
occurring more than 90 days of the completion of treatment. The time to late grade 2+ or 3+
adverse events will be measured from the time protocol treatment started to the time of the
worst late grade 2+ or 3+ adverse event, respectively. If no such late adverse event is
observed until the time of the analysis, the patient will be censored at the time of the analysis.
The distribution of time to late grade 2+ or 3+ adverse events will be estimated using the
Kaplan-Meier method109 and tested using a one-sided log-rank test110-111 with the significance
level of 0.025 for each hypothesis. A multivariate Cox regression model115 will be used to
compare the treatment differences of time to late adverse event. Both unadjusted and adjusted
hazard ratios (H1: Arm 1 vs. Arm 2 and H2: Arm 2 vs. Arm 3, respectively) and the respective
97.5% confidence interval will be computed. Treatment arm, SV involvement, prostatectomy
Gleason score, pre-radiotherapy PSA, pathology stage, age, and race (as appropriate) will be
adjusted for in this analysis.
42
RTOG 0534
13.5.5
A Chi-square test will be used at a significance level of 0.05 to test the correlation between the
common toxicity categories in the American Urological Association Symptom Index (AUA SI)
and urinary morbidity (Adverse Event terms: Urinary frequency/urgency) using the CTCAE v.
3.0.
Modeling the Relationship of Genomic and Proteomic Biomarkers to the Study Endpoints
(1/8/09)
At the time of data maturity of this study, we will propose specific details of the markers to be
investigated. We will address the assays that will be used and a list of specific correlative aims
with appropriate statistical considerations. The following is a general guideline for the statistical
consideration for this analysis. This analysis will be done in each arm separately to test the
prognostic vales of biomarkers.
A genomic or proteomic biomarker will be categorized into two subgroups based upon
previously defined (or hypothesized) cut-off points and these two groups will be referred to as
favorable and unfavorable risk groups. The patients with genomic and proteomic biomarkers
will be compared with the patients without a value for that biomarker to determine if there are
any differences with respect to distribution of baseline variables (SV involvement,
prostatectomy Gleason score, pre-radiotherapy PSA, and pathology stage). We want to know
if there is a difference in survival rate between these two groups. The null (H0) and alternative
(HA) hypotheses for survival distribution (S) are
H0: S0 (t) ≥ S1(t) vs. HA: S0 (t) < S1(t) , where t is time
Tests will be performed to see if one group is statistically significantly better than the other in
the primary endpoint and secondary endpoints that are related to time to failure (hormone
refractory disease, distant metastasis, cause-specific survival, and overall survival). However,
the selection of the cut-off point for each biomarker is not established. If the hypothesized cutoff points do not yield statistical significance, other cut-off points may be evaluated. Therefore,
various cut-off points are evaluated for their statistical significance. To correct the problem from
the multiple testing, the Bonferroni correction will be used. The overall survival functions will be
estimated by the Kaplan-Meier method and will be tested for the overall survival difference
between the favorable and unfavorable groups using the log-rank test. We will use the causespecific hazard rate approach106 to estimate other survival/failure distributions and test the
survival/failure difference between the two groups using the cause-specific log-rank test. The
multivariate analysis will be performed using the Cox proportional hazards model115 for both
groups. Potential covariates evaluated for the multivariate models are SV involvement,
prostatectomy Gleason score, pre-radiotherapy PSA, pathology stage, and assigned treatment.
A stepwise procedure will be used to develop the base model for each outcome endpoint prior
to evaluating the prognostic impact of the biomarkers. This approach will be employed to
account for as much variation as possible for each outcome before it is tested. It is entirely
possible that factors shown to be prognostic in other published series may not be found
prognostic here.
If high-dimensional data, such as two-color Microarray data, are generated from blood/urinebased proteomic and genomic data, the following guideline could be applied for the data preprocessing. A careful examination of array images of each gene’s spots on the array images
will be carried out to find the spots affected by experiment artifacts. This is a general guideline
for the statistical consideration for the two-color Microarray data analysis.
We will not include genes whose intensity is less than 100116-117 n both green and red
intensities. Local background hybridization signals will be subtracted from the intensities. Let R
j
be the background-adjusted fluorescence intensity for the cancer or benign sample and G be
j
the background-adjusted fluorescence intensity for the reference sample for gene j on a
particular array. The gene expression ratio is computed as R /G and undergoes normalization
j
j
and transformation to the log-2 scale. Normalization will be applied to remove systematic
differences due to extraneous factors such as array effects, global dye effects, print tip effects,
etc. Simple normalization methods such as global median centering116 will be considered as
well as more complex methods such as print tip-specific corrections and intensity-based
43
RTOG 0534
normalization methods such as lowess smoothing118 if diagnostic plots (e.g., M vs A plots119)
suggest they are needed. These log-transformed, normalized gene expression ratios are used
as the basic data in subsequent analyses. If one of the two intensities in a spot is less than
100, that intensity will be set to 100. Genes with greater than 20% of spots missing intensities
will be removed from the analysis. For remaining genes, individual missing log ratio values will
be imputed using the k-nearest neighbors approach, with k = 10.120
The high-dimensional data from patients who yield both pre- and post-treatment tissue
specimens will be used to see the gene expression difference. Let m be the number of genes
that will be tested. Let d be the gene expression difference between pre- and post- treatment
iij
for patient i and gene j on a treatment arm. Denote the mean difference between pre- and posttreatment gene expression for gene j as D . A test will be conducted to test the following null
j
(H ) and alternative (H ) hypotheses for each gene:
0
A
H : D = 0 vs. H : D ≠ 0
0
13.5.6
j
A
j
We will control the false discovery proportion when a test for a gene is called significant. A
paired t-test will be used to calculate the unadjusted univariate p-value for each gene. We will
identify all genes with adjusted p-values121 ≤ 0.05 as being differentially expressed between
pre- and post-treatment to be 95% confident that the false discovery proportion is no more than
10%.
Analysis for Endpoints Related to Quality of Life (QOL) [2/13/08] [1/8/09]
Patient accrual for the QOL measurements will be limited to 200 cases in each arm.
We will use seven instruments to assess quality of life (QOL): the Expanded Prostate Cancer
Index (EPIC), EPIC Sexual Medications/Devices Supplement (Utilization of Sexual
Meds/Devices), the 25-item version of the Hopkins Symptom Checklist (HSCL-25), the EuroQol
(EQ-5D), Hopkins Verbal Learning Test-Revised (HVLT-R), Trail Making Test, parts A & B, and
the Controlled Oral Word Association Test (COWAT). Protocol eligible patients will be included
in the QOL analysis only if they agree to participate in the QOL portion of this study. All the
QOL instruments (EPIC, Utilization of Sexual Meds/Devices, HSCL-25, EQ-5D, HVLT-R, Trail
Making Test, parts A & B, and COWAT) will be collected on all cases participating in the trial.
To minimize missing QOL data, we have included detailed instructions for collection of QOL
and what to do if the patient misses a scheduled assessment, and RTOG provides
individualized patient calendars available to Investigators and Research Associates 24/7 on the
RTOG web site.
We will describe the distributions of QOL data collection patterns over all collection points in
each treatment arm. Longitudinal data analysis, specifically the general linear mixed-effect
model122 will be performed to describe the change trend of the EPIC, Utilization of Sexual
Meds/Devices, HVLT-R, Trail Making Test parts A & B, COWAT, HSCL-25, and EQ-5D scores
over time across the three treatments. The primary objective in HRQOL analysis is to
determine the QOL differences. The response will be the change of measurement from
baseline for each measurement. The model will include the baseline and stratification variables
(SV involvement, prostatectomy Gleason score, pre-radiotherapy PSA, pathology stage).
The EPIC and HSCL-25 will be collected at pretreatment (baseline), the end of RT, and at 1
year and 5 years after therapy starts. Patient self-assessment of symptoms will be performed
using four primary EPIC domains: urinary, bowel, sexual, and hormonal symptoms. The data
about the use of erectile aids from Utilization of Sexual Meds/Devices will be reported along
with question 17-b in the EPIC. The HSCL-25 has 25 items and is scored by a four point Likert
scale (1-not at all, 2-a little, 3-quite a bit, and 4-extremely). A higher score means a worse
mood or depression. The HVLT-R, Trail Making Test, parts A & B, and COWAT will be
collected at pretreatment (baseline), the end of RT, and at 1 year after the therapy starts. There
are three immediate recall responses, one delayed recall response, and one delayed
recognition response in the HVLT-R. The response is the number of words the patient can
recall out of 12 words for recall responses and the difference of the listed words correctly and
incorrectly recalled for recognition response. The response from Trail Making Test, parts A & B
is the time takes to finish each test less than 3 and 5 minutes, respectively. There are three
responses for the COWAT, and each response is the number of words starting with a provided
letter of the alphabet that the patient can produce in one minute. The EQ-5D will be collected
at pretreatment (baseline), at 1 year and 5 years after therapy starts. The EQ-5D is a two-part
44
RTOG 0534
self-assessment questionnaire. The first part consists of 5 items covering 5 dimensions
(mobility, self care, usual activities, pain/discomfort, and anxiety/depression). Each dimension
is measured by a three point Likert scale (1-no problems, 2-moderate problems, and 3-extreme
problems). There are 243 (=35) health states. The second part is a visual analog scale (VAS)
valuing the current health state measured by 100 point scale with 10 point interval (0-worst
imaginable health state, 100-best imaginable health state). The QOL Co-Chair, Dr. Bruner, will
review and specify the VAS score for each case. We will transform the 5-item index score and
VAS score into a utility score between 0 (Worst health state) and 1 (Best health state) for
comparative purposes.
We hypothesize that the measurements from EPIC, HVLT-R, Trail Making Test, parts A & B,
and COWAT will be worse in the arms with NC-STAD than in the PBRT arm. We also
hypothesize that measurements from HSCL-25 will be lower in the arms with NC-STAD than in
the PBRT arm. For all QOL analyses, we will conduct two comparisons between the two
treatment arms (Arm 1 vs. Arm 2 and Arm 1 vs. Arm 3) with a two-sided test. The significance
level α for the pair-wise comparison will be adjusted by the Bonferroni method123 to α =0.05/2 to
maintain the overall significance level of α =0.05. To address the non-ignorable missing data
caused by censoring survival time, the data analysis also will include patients who have not
died.
The required sample size per treatment arm when we use 1 domain is 64 with 80% statistical
power and 86 with 90% statistical power, respectively, based on an effect size of 0.5 according
to the EPIC web site.124 The required sample size per treatment arm when we use 4 domains is
91 with 80% statistical power and 116 with 90% statistical power, respectively, based on an
effect size of 0.5. Therefore, there will be sufficient statistical power to detect a difference of
0.5 in four domain scores of HRQOL measurements in the EPIC instrument among the
treatment arms. Because the participation rate in QOL assessments will be less than 100%, the
expected sample size for the QOL analysis must be adjusted according to the participation
rate. Table 11 shows adjusted sample sizes for a range of participation rates. Considering the
possible low response rate, 200 cases per arm are required. Accrual for the QOL studies will
be limited to 200 cases per randomization arm.
Table 11: Adjusted sample size* per treatment with four domains in EPIC
RESPONSE RATE
80% POWER
90% POWER
100%
91
116
90%
102
129
80%
114
145
70%
130
166
60%
152
194
*The sample size is calculated by dividing the sample size at 100% by participation rate
To examine trade-offs between the survival time and QOL, we will combine them for each
patient into two single measurements: Quality Adjusted Life Year (QALY) and Quality Adjusted
FFP Year (QAFFPY). If (and only if) the primary endpoint hypothesis is substantiated, we will
conduct a cost-utility analysis. The cost-utility analysis will not be done until after the primary
endpoint results are published. QALY and QAFFPY are defined by the weighted sum of
different time episodes added up to a total quality-adjusted survival time and a total qualityadjusted FFP time, respectively. These health state-based methods of quality-adjusted
survival analysis are known as Q-TwiST,79 the quality-adjusted time without symptoms and
toxicity method.
Q-TwiST = ∑i=1k qi si
45
RTOG 0534
where qi is the quality (the utility coefficient) of health state i, si is the duration spent in each
health state, and k is the number of health states. We will use Glasziou’s multiple health-state
(Q-TwiST) models125 to use the repeated measures of EQ-5D. Because Glasziou’s method
incorporates longitudinal QOL data into an analysis of quality-adjusted survival, the healthstated model must be constructed on the following assumptions:
A1) QOL is independent from treatment.
A2) A health state is independent from previous states.
A3) Proportionality of quality-adjusted duration and duration of the actual state of a health
state.
Assumption A1 can be checked by plotting QOL over time according to treatment, and the ttest can be used to compare the mean QOL scores of each treatment arm. Assumption A2 can
be checked by comparing the QOL for patient groups in a given health state where the groups
are defined by duration of previous health state experience using a regression model. Suitable
checks for assumption A3 at minimum would be a simple plot. If data does not support these
assumptions, we will use a method which uses the longitudinal QOL data directly.
The Medicare reimbursement in dollars/QALY and the Medicare reimbursement in
dollars/QAFFPY will be calculated as a function of the monetary cost per relative value of each
health state and its duration. Cost-utility will be analyzed at two time points: at 1 year and 5
years post-therapy. We will use the five-item utility score in EQ-5D for the cost-utility analysis.
We will use the z-test to test the hypothesis that the cost-utility in the two treatment arms (Arm
1 vs. Arm 2 and Arm 1 vs. Arm 3) is the same with significance level of 0.05/2=0.025 and a
two-sided test. We will compare the cost-utility using the Medicare reimbursement in
dollars/QALY and the Medicare reimbursement in dollars/QAFFPY between the two treatment
arms after adjusting for the baseline and stratification variables.
We will evaluate the cost-utility of the treatment arm in terms of the primary outcome and will
also compare the cost-utility among the three treatment arms. The cost-utility analysis will only
include patients whose care are reimbursed under the federal Medicare payment system but
will exclude those in Medicare HMOs as well as those under alternative federal coverage
(including Medicaid, DOD, and the VA) as well as those covered by private payers or other
payment systems. Cost-utility will be analyzed for planned publication at two time-points:
looking at initial treatment costs and quality of life at 1 year post-therapy and at 5 years posttherapy. The cost-utility analysis will not be done until after the primary endpoint results are
published. We will use the 5-item utility score in EQ-5D for the cost-utility analysis and the
Medicare costs defined as in Section 1.6.3. The Medicare cost in dollars/QALY will be
calculated as a function of the monetary cost per relative value of each health state and its
duration. We will use Analysis of Variance (ANOVA) to compare the cost-utility among the
three treatment arms at a significance level of 0.05. If there is a statistically significant
difference, a Z-test will be used to compare it between each combination of two treatment arms
(Arm 1 vs. Arm 2 and Arm 1 vs. Arm 3, and Arm 2 and Arm 3) after adjusting for the baseline
and stratification factors with a significance level of 0.05/3=0.017 and a two-sided test.
A multivariate regression model will be used to model the association between serum levels of
beta-amyloid (Abeta) and measures of the HVLT-R, Trail Making Test, parts A & B, COWAT,
and HSCL-25, respectively. The model will include at least the baseline and stratification
factors (SV involvement, prostatectomy Gleason score, pre-radiotherapy PSA, pathology
stage) as covariates.
To inspect the missing data mechanism, we will use at least a graphical method. A missing
completely at random (MCAR) mechanism exists when missing values are randomly distributed
across all observations. A missing at random (MAR) mechanism exists when values are not
randomly distributed across all observations, rather than one or more sub-samples. If the
cause of missing data is MCAR, listwise deletion (complete case analysis) will be done. If the
MAR assumption is supported by the data, then an imputation method such as multiple
imputation will be applied to impute missing data. If the MAR assumption is not supported by
the data, then adjusting for covariates (such as the baseline QOL score) might reduce the
conditional association between outcomes and missing values. If missing data patterns look
similar when stratified by such covariate(s), then an analysis that adjusts for such covariate(s)
46
RTOG 0534
13.5.7
will be conducted and an imputation method such as multiple imputation will be applied. If
approximate conditional independence cannot be obtained with any set of covariates, then
MNAR (missing not at random) must be addressed by an explicit model for the missing data
mechanism126 and then an imputation method such as multiple imputation will be applied. All
results from the imputed analysis using the multiple imputation will be compared to the
complete case analysis results to assess any potential biases. We will conduct a sensitivity
analysis using various assumptions on the missing data to determine what impact missing data
and imputation methods have on the study conclusions. Imputation methods when prescribed
by validated instrument developers will be employed first. Additional methods or methods used
when none are described for a given instrument may include: worst-case scenario (in which
missing data are assumed to be unfavorable for those on the experimental treatment and
favorable of those in the control group); use of the mean response for individual patients who
withdrew from the trial from either all or similar (matched) patients remaining in the trial; last
observation carried forward (LOCF) [using the last observation as the final observation]; or
linear mixed-effects models, to obtain separate estimates for the QOL outcome within strata
based on missing data patterns.126-127 RTOG recognizes that all options are subject to bias and
analysis of more than one method for consistency across methods is prudent.
Group Sequential Testing for Early Termination and Reporting of Efficacy and Futility (1/8/09)
A group sequential test with three planned interim analyses and a final analysis will be
performed. The interim analysis will be carried out when the cumulative accrual (patients
whose follow-up is at least 5 years from the randomization date) are met. For each interim
analysis, one efficacy and two futility tests will be carried out. At each planned interim analysis,
the p-value from the Z-test statistics, eq.1, for the difference between the two FFP rates
assessing treatment efficacy or futility with respect to the primary endpoint will be compared to
the nominal significance level. The significance level of 0.001, which is similar to the HaybittlePeto test104-105, was chosen for efficacy testing. For the futility testing boundary, we will use a
less aggressive boundary, Rule C in Freidlin and Korn.106
We will first compare Arm 3 with Arm 2 and choose the arm that has the higher FFP rate (if
they are the same, Arm 2 will be chosen). Let p1, p2, and p3 equal the rate of 5-year FFP of
Arm 1, Arm 2 and Arm 3, respectively. If Arm 2 is better than Arm 3 2(p2 ≥ p3), then we
compare Arm 2 with Arm 1. The following hypotheses are tested.
H02: p2≤ p1 vs. HA2: p2 > p1
If the H02 is rejected (p-value ≤ 0.001), then we conclude that the 5-year FFP of Arm 2 will be
better than Arm 1. We report that Arm 2 is the best and stop accrual if applicable. If the H02 is
not rejected (p-value > 0.001), then we continue the trial.
If Arm 3 is better than Arm 2 (p2 < p3), then we compare Arm 3 with Arm 1. The following
hypotheses are tested.
H02: p3 ≤ p1 vs. HA2: p3 > p1
If the H02 is rejected (p-value ≤ 0.001), then we conclude that the 5-year FFP of Arm 3 will be
better than Arm 1. We report that Arm 3 is the best and stop accrual if applicable. If the H02 is
not rejected (p-value > 0.001), then we continue the trial.
For futility testing, we compare Arm 3 vs. Arm 1 and Arm 2 vs. Arm 1 if applicable. The
H01: p1 ≥ p2 vs. HA1: p1 < p2 and H03: p1 ≥ p3 vs. HA3: p1 < p3
The alternative hypotheses, HA1 (p1 = p2 + 0.1) and HA3 (p1 = p3 + 0.1) will be tested at
0.001 level (the futility nominal significance level). If the computed p-value is less than 0.001
then we will consider stopping the trial in favor of H01 or H03 and report the results. If we stop
the trial for futility, then we will conclude that the 5-year FFP of Arm 1 will be better than Arm 2
or Arm 3 and continue the trial for the other two remaining arms. Otherwise, we will continue
the trial.
47
RTOG 0534
Table 12: The Schedule for the Planned Interim Analysis
Information
Estimated
Cumulative
Time
Analysis Time*
Accrual in the
Three Arms**
0.25
7 years
397
0.50
9 years
794
0.75
11 years
1191
1.0
13 years
1587
* Time to the interim analysis from the first patient entry without considering ineligibility or lackof-data rate
**The number of eligible patients whose follow-up is at least 5 years from the randomization
date
13.6
13.7
13.8
Based on the results of each interim analysis, the following action will be taken and the
responsible statistician will recommend to the RTOG DMC that the randomization be
discontinued, if applicable, and the study be considered for early publication. Before making
such a recommendation, the accrual rate, treatment compliance, safety of the treatments, and
the importance of the study are taken into consideration along with the p-value. The RTOG
DMC will then make a recommendation about the trial to the RTOG Group Chair.
Interim Report to Monitor the Study Progress
Interim reports with descriptive statistics will be prepared twice per year until the initial paper
reporting the treatment results has been submitted. In general, the interim reports will contain
information about the patient accrual rate with a projected completion date for the accrual phase,
compliance rate of treatment delivery with the distributions of important prognostic baseline
variables, and the frequencies and severity of the adverse event by treatment arm. The interim
reports will not contain the results of the treatment comparisons with respect to the primary
endpoint and secondary endpoints. This study will be monitored by the Clinical Data Update
System (CDUS) version 3.0. Cumulative CDUS data will be submitted quarterly by electronic
means. Reports are due January 31, April 30, July 31, and October 31.
Reporting the Initial Treatment Analysis (1/8/09)
The analysis reporting the treatment results will be carried out after the criteria for early
stopping/reporting are met. Three interim comparisons and one final analysis will be performed
for efficacy and futility of the experimental treatment will be carried out as described in section
13.5.7. The Z-test statistics for the difference between the two rates with the standard errors
estimated by Greenwood’s method, eq. (1), will be used with an overall significance level of
0.025. It will include tabulation of all cases entered and those excluded from the analyses; the
distribution of the important prognostic baseline variables; safety treatments; treatment
compliance; and observed results with respect to the primary and secondary endpoints will be
shown. All eligible patients randomized will be included in the comparison and will be grouped by
assigned treatment in the analysis (intent-to-treat analysis). In addition, exploratory analyses of
treatment comparisons of the primary and secondary survival endpoints will be tested using the
Cox proportional hazard model114 that includes treatment arms, the stratification factors (SV
involvement, prostatectomy Gleason score, pre-radiation PSA level, and pathology stage), age,
and race (as appropriate).
Gender and Minorities
In conformance with the National Institute of Health (NIH) Revitalization Act of 1993 with regard
to inclusion of women and minorities in clinical research, Participation rates of men will be
examined in the interim analyses. Based on the accrual statistics from RTOG 94-08, we project
that 81% of the men in the study are White, 15% are Black or African American, 3% are Hispanic,
0.5% are Asian, 0.3% are Pacific Islander and 0.2% are American Indian or Alaskan Native. The
following table lists the projected accrual by race/ethnicity.
48
RTOG 0534
Projected Distribution of Gender and Minorities
Ethnic Category
Hispanic or Latino
Not Hispanic or Latino
Ethnic Category: Total of all subjects
Females
N/A
N/A
N/A
Racial Category
American Indian or Alaskan Native
Asian
Black or African American
Native Hawaiian or other Pacific Islander
White
Racial Category: Total of all subjects
Females
N/A
N/A
N/A
N/A
N/A
N/A
49
Gender
Males
53
1711
1764
Gender
Males
6
9
251
4
1494
1764
Total
53
1711
1764
Total
6
9
251
4
1494
1764
RTOG 0534
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APPENDIX I
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Informed Consent Template for Cancer Treatment Trials
(English Language)
A Phase III Trial Of Short Term Androgen Deprivation With Pelvic Lymph Node Or
Prostate Bed Only Radiotherapy (SPPORT) In Prostate Cancer Patients
With A Rising PSA After Radical Prostatectomy
This is a clinical trial, a type of research study. Your study doctor will explain the clinical trial to you. Clinical
trials include only people who choose to take part. Please take your time to make your decision about taking part.
You may discuss your decision with your friends and family. You can also discuss it with your health care team.
If you have any questions, you can ask your study doctor for more explanation.
You are being asked to take part in this study because you have had surgery to remove your prostate and your
study doctor has recommended radiation therapy because your blood level of Prostate Specific Antigen (PSA)
has been going up. (The PSA is a value that helps determine the aggressiveness of your prostate cancer.)
Why is this study being done?
The purpose of this study is to compare the effects, good and/or bad of three treatment methods on participants
and their cancer.
External beam radiation therapy is one of the standard treatments for men with prostate cancer who have a rising
PSA after surgery. Different methods of radiation therapy are used, and it is not known which one is best. Most
commonly, the area where the prostate was originally located before being removed (the prostate bed) is treated,
without treating the lymph nodes in the pelvis. Prostate cancer can spread to the lymph nodes. There is some
evidence in men who have not had surgery that radiotherapy to the pelvic lymph nodes may stop the cancer from
spreading under some conditions. Since treating the pelvic lymph nodes can result in increased side effects, the
benefit of this method of radiation therapy needs to be tested.
Prostate cancer feeds on male hormones, such as testosterone. Drugs that reduce or block testosterone
(hormone therapy) can cause some prostate cancer cells to die and others to become sick so that they don’t
grow. Some patients treated with a combination of these drugs and radiation have a greater chance of not having
the cancer return when compared to men treated with radiation alone. These studies were done in men who did
not have surgery. Since hormone therapy can result in increased side effects, the benefit of combining hormone
therapy with radiation therapy needs to be tested.
There are 3 treatment groups in this study:
1) Patients who receive radiation therapy to the prostate bed only;
2) Patients who receive hormone therapy for 4 to 6 months plus radiation therapy to the prostate bed;
3) Patients who receive hormone therapy for 4 to 6 months plus radiation therapy to the prostate bed and to the
pelvic lymph nodes.
If you agree to participate in this study, you will receive one of these 3 treatments.
How many people will take part in the study?
About 1,764 people will take part in this study.
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What will happen if I take part in this research study? (01/8/09) (3/24/10)
Before you begin the study:
You will need to have the following exams, tests or procedures to find out if you can be in the study. These
exams, tests or procedures are part of regular cancer care and may be done even if you do not join the study. If
you have had some of them recently, they may not need to be repeated. This will be up to your study doctor.
 Review of the tissue from your prior surgery to remove your prostate to determine your Gleason score (a
value that helps determine the aggressiveness of your prostate cancer)
 History and physical exam, including a digital rectal exam (DRE) and an assessment of your ability to carry
out activities of daily living (which will include questions such as whether you are able to feed, bathe, and
dress yourself).
 You will be asked to fill out a questionnaire on urinary symptoms and function called the American Urological
Association Symptom Index (AUA SI).
 A blood test to determine your PSA (a value that helps determine the aggressiveness of your prostate
cancer). About 2 teaspoons of blood will be drawn from a vein. At least two PSA tests spaced by 2 months
must be obtained after surgery to remove the prostate. Your study doctor also may draw another PSA before
the start of treatment for a baseline value.
 Other blood tests (for blood count, liver function, and to measure testosterone)
 A CT (Computed Tomography) scan or MRI (Magnetic Resonance Imaging) of your pelvis to determine if
there is any evidence of cancer spread to the pelvic lymph nodes. A CT scan is a study using x-rays to look at
one part of your body. An MRI is imaging using a strong magnetic field to look at one part of your body.
 A bone scan to determine if the cancer has spread to the bones.
 A CT scan with an urethrogram or an MRI for radiation treatment planning may be ordered; for a urethrogram,
a tube is placed into the opening of the canal (at the end of the penis) from which urine is emptied from the
body. Dye is injected, and images are taken.
You will be "randomized" into one of the study groups described below. Randomization means that you
are put into a group by chance. A computer program will place you in one of the study groups. Neither
you nor your study doctor can choose the group you will be in. You will have a one in three chance of
being placed in any group.
If you are in group 1 (often called "Arm 1"): You will receive radiation treatments to the prostate bed
once daily, 5 days a week, Monday through Friday, for a total of 36 to 39 treatments (the exact number
will be decided by your study doctor). Each radiation treatment will take 15-30 minutes.
If you are in group 2 (often called "Arm 2"): You will receive radiation treatments to the prostate bed
once daily, 5 days a week, Monday through Friday, for a total of 36 to 39 treatments (the exact number
will be decided by your study doctor). Each radiation treatment will take 15-30 minutes.
You also will receive hormone therapy for 4 to 6 months (the exact length will be decided by your doctor).
The hormone therapy will begin 2 months before the start of the radiation treatments. There are two parts
to the hormone therapy. You will take injections either under the skin or in the muscle, and you will take a
pill, either flutamide three times per day or bicalutamide once per day. The pills will be taken for at least 4
of the 6 months.
If you are in group 3 (often called "Arm 3"): You will receive radiation treatments to the pelvic lymph
nodes and prostate bed once daily, 5 days a week, Monday through Friday, for 25 treatments. From that
point on, the radiation treatments will target the prostate bed only, 5 days per week, for another 11-14
treatments. The total number of radiation treatments will be 36 to 39 treatments (the exact number will be
decided by your study doctor). Each radiation treatment will take 15-30 minutes.
You also will receive hormone therapy for 4 to 6 months (the exact length will be decided by your study
doctor). The hormone therapy will begin 2 months before the start of the radiation treatments. There are
two parts to the hormone therapy. You will take injections either under the skin or in the muscle, and you
will take a pill, either flutamide three times per day or bicalutamide once per day. The pills will be taken
for at least 4 of the 6 months.
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After entering the study and prior to radiotherapy: (1/8/09)
If the exams, tests and procedures show that you can be in the study, and you choose to take part, then you will
need the following tests and procedures if you are randomized to receive hormone therapy (Groups 2 and 3).
They are part of regular cancer care.
 After 2 months of hormone therapy and before radiation therapy, blood will be drawn (for a blood count, liver
function, and to measure testosterone and PSA).
 After 2 months of hormone therapy and before radiation therapy, you will be requested to fill out an American
Urological Association Symptom Index (AUA SI) questionnaire.
During Radiation Therapy: (1/8/09)
 Weekly during radiation therapy: History and physical exam, including an assessment of your ability to carry
out activities of daily living, and assessment of any side effects you may be experiencing from the treatment
 Blood will be drawn during the 6th (last) week of radiotherapy (for a blood count, liver function and to measure
testosterone).
 You will be asked to fill out an American Urological Association Symptom Index (AUA SI) questionnaire in the
6th week of radiation therapy.
When you are finished receiving radiation: (1/8/09)
You will need these tests and procedures:
 At 6 weeks (1.5 months), 3, and 6 months following the completion of radiation: blood tests to measure liver
function; at 3 and 6 months following the completion of radiation: blood will be drawn for blood count
 At 3, 6, and 12 months following the completion of radiation, every 6 months for the next 6 years, and then
annually: History and physical exam, including a digital rectal exam (DRE), an assessment of your ability to
carry out activities of daily living, an assessment of any side effects from the treatments, and an AUA-SI
questionnaire.
 A PSA and testosterone will be checked at 6 weeks (1.5 months), 3 months, 6 months, 9 months, and 12
months following completion of radiotherapy; at 3-month intervals for the next year; and then at 6-month
intervals thereafter.
 If something is felt in the prostate bed that is suspicious for recurrence, your study doctor will request a
needle biopsy to evaluate this.
 If your PSA rises at any time after completion of treatment, your study doctor may order a bone scan and CT
scan or MRI of the abdomen and pelvis.
Study Plan
Another way to find out what will happen to you during the study is to read the chart below. Start reading at the
top and read down the list, following the lines and arrows.
Randomize
(You will be in one of three Groups)
Group 1
Radiation to the Prostate Bed
(36-39 Treatments)
Group 2
(36-39 Treatments)
Plus Hormone Therapy
(4-6 months)
60
Group 3
Radiation to the Pelvic Lymph
Nodes and the Prostate Bed
(25 Treatments)
Only (11-14 Treatments)
Plus Hormone Therapy
(4-6 months)
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How long will I be in the study? (1/8/09)
You will receive 36–39 radiation treatments over 7–8 weeks. Hormone therapy, if given, will last 4–6 months.
After you are finished receiving radiation therapy, the study doctor will ask you to visit the office for follow-up
exams at 3, 6, and 12 months after radiotherapy, then every 6 months for the next 6 years, and annually
thereafter. The study doctors would like to keep track of your medical condition by seeing you every year for your
lifetime.
Can I stop being in the study?
Yes. You can decide to stop at any time. Tell the study doctor if you are thinking about stopping or decide to
stop. He or she will tell you how to stop safely.
It is important to tell the study doctor if you are thinking about stopping so any risks from the radiation and
hormone therapy (if given) can be evaluated by him/her. Another reason to tell your study doctor that you are
thinking about stopping is to discuss what follow-up care and testing could be most helpful for you.
The study doctor may stop you from taking part in this study at any time if he/she believes it is in your best
interest; if you do not follow the study rules; or if the study is stopped.
What side effects or risks can I expect from being in the study?
(1/8/09) You may have side effects while on the study. Everyone taking part in the study will be watched carefully
for any side effects. However, researchers don’t know all the side effects that may happen. Side effects may be
mild or very serious. Your health care team may give you medicines to help lessen side effects. Many side effects
go away soon after you stop radiation or hormone therapy (if given). In some cases, side effects can be serious,
long lasting, or may never go away. In addition, some of the side effects may be life threatening and, in rare
instances, may cause death. The risks of side effects related to the radiation may be higher in group 3, which
includes the treatment of the pelvic lymph nodes.
You should talk to your study doctor about any side effects that you have while taking part in the study.
Risks and side effects related to the radiation therapy include those which are:
Likely (1/8/09)
 Tanning, redness, or darkening of skin in treatment area
 Rash, itching or peeling of skin
 Temporary hair loss in the treatment area
 Temporary fatigue
 Abdominal cramps
 Frequent bowel movements, sometime with urgency, or diarrhea
 Rectal cramps and irritation with pain on defecation
 Mild rectal bleeding that does not require treatment
 Bladder irritation with a stinging sensation
 Frequency or urgency of urination
 Small amounts of blood in the urine
Less Likely
 Urinary obstruction requiring the placement of a temporary urinary catheter and/or dilatation because of
stricture (narrowing)
 Less ability to control urine (increased incontinence)
 Inability to achieve an erection (inability of the penis to become hard)
 Rectal bleeding that requires medication or laser treatment to stop
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Rare but serious (1/8/09)
 Injury to the bladder, urethra, bowel, or other tissues in the pelvis or abdomen requiring additional
procedure or surgery, such as a colostomy (bag for stool).
 Intestinal obstruction requiring surgery
Risks and side effects related to the hormone therapy those which are:
Likely (1/8/09)
 Hot flashes
 Inability to achieve an erection (inability of the penis to become hard)
 Loss of sex drive
 Mood swings
 Muscle loss, weakness and fatigue
 Mild anemia (drop in red blood cell count)
 Weight gain
 Bone weakening
Less Likely (1/8/09)
 Significant bone loss (osteopenia or osteoporosis) which could result in fracture
 Significant anemia
 Blood sugar problems (diabetes)
 High fats and cholesterol in your blood (hyperlipidemia)
 Blood vessel disease (arteriosclerosis, heart failure)
 Fluid retention and ankle swelling (edema)
 Breast enlargement and tenderness
 Difficulty with calculations and memory (verbal recall, cognition)
Rare and Possibly Serious (11/23/11)
 Liver damage (hepatitis)
 Flare up in arthritis
 Bone fracture
 Depression
 Increased long-term risk of developing diabetes
 Increased long-term risk of cardiovascular disease
 Death due to heart disease
Patients receiving treatment with LHRH agonists should undergo periodic monitoring of blood glucose and/or
glycosylated hemoglobin (HbA1c) for signs of developing diabetes or worsening of blood glucose control in
patients with diabetes, and also for the signs and symptoms suggestive of the development of cardiovascular
disease.
Reproductive risks: You should not father a baby nor donate sperm while on this study or during the first 3
months after cessation of therapy because the drugs and radiation in this study can affect an unborn baby. Check
with your study doctor about what kind of birth control methods to use and how long to use them. Some methods
might not be approved for use in this study. Some of the drugs and radiation used in this study may make you
unable to have children in the future.
For more information about risks and side effects, ask your study doctor.
Are there benefits to taking part in the study?
Taking part in this study may or may not make your health better. It is not known whether the combination of
radiation to the prostate bed plus hormone therapy is better than radiation to the prostate bed alone. Also, it is not
known whether radiation to the pelvic lymph nodes and prostate bed plus hormone therapy is better than
radiation to the prostate bed only combined with hormone therapy. We do know that the information from this
study will help researchers learn more about how best to treat men who have a rising PSA after surgery to
remove their prostate. This information could help future cancer patients.
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RTOG 0534
What other choices do I have if I do not take part in this study?
Your other choices may include:
 Getting treatment or care for your cancer without being in a study; this could include the following options,
either alone or in combination with each other:
o External beam radiation therapy (typically, to the prostate bed)
o External beam radiotherapy plus hormone therapy
o Hormone therapy
 Taking part in another study
 Getting no treatment (With this choice, your tumor could continue to grow and your disease could spread)
Talk to your study doctor about your choices before you decide if you will take part in this study.
Will my medical information be kept private? (11/23/11)
Data are housed at RTOG Headquarters in a password-protected database. We will do our best to make sure
that the personal information in your medical record will be kept private. However, we cannot guarantee total
privacy. Your personal information may be given out if required by law. If information from this study is published
or presented at scientific meetings, your name and other personal information will not be used.
Organizations that may look at and/or copy your medical records for research, quality assurance, and
data analysis include:
 The Radiation Therapy Oncology Group
 The National Cancer Institute (NCI) and other government agencies involved in keeping research safe for
people, like the Central Institutional Review Board (CIRB) and the Food and Drug Administration (FDA)
 The Cancer Trials Support Unit (CTSU), a research group sponsored by the National Cancer Institute (NCI)
to provide greater access to cancer trials [for CTSU participants only]
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S.
Law. This web site will not include information that can identify you. At most, the Web site will include a
summary of the results. You can search this Web site at any time.
[Note to Informed Consent Authors: the above paragraph complies with the new FDA regulation found at 21 CFR
50.25(c) and must be included verbatim in all informed consent documents. The text in this paragraph cannot be
revised.]
What are the costs of taking part in this study?
You and/or your health plan/ insurance company will need to pay for some or all of the costs of treating your
cancer in this study. Some health plans will not pay these costs for people taking part in studies. Check with
your health plan or insurance company to find out what they will pay for. Taking part in this study may or may not
cost your insurance company more than the cost of getting regular cancer treatment.
You will not be paid for taking part in this study.
For more information on clinical trials and insurance coverage, you can visit the National Cancer
Institute’s Web site at http://cancer.gov/clinicaltrials/understanding/insurance-coverage. You can print a
copy of the “Clinical Trials and Insurance Coverage” information from this Web site.
Another way to get the information is to call 1-800-4-CANCER (1-800-422-6237) and ask them to send you
a free copy.
What happens if I am injured because I took part in this study?
It is important that you tell your study doctor, __________________ [investigator’s name(s)], if you feel that you
have been injured because of taking part in this study. You can tell the study doctor in person or call him/her at
__________________ [telephone number].
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You will get medical treatment if you are injured as a result of taking part in this study. You and/or your health
plan will be charged for this treatment. The study will not pay for medical treatment.
What are my rights if I take part in this study?
Taking part in this study is your choice. You may choose either to take part or not to take part in the study. If you
decide to take part in this study, you may leave the study at any time. No matter what decision you make, there
will be no penalty to you and you will not lose any of your regular benefits. Leaving the study will not affect your
medical care. You can still get your medical care from our institution.
We will tell you about new information or changes in the study that may affect your health or your willingness to
continue in the study.
A Data Safety Monitoring Board will be regularly meeting to monitor safety and other data related to this study.
The Board members may receive confidential patient information, but they will not receive your name or other
information that would allow them to identify you by name.
In the case of injury resulting from this study, you do not lose any of your legal rights to seek payment by signing
this form.
Who can answer my questions about the study?
You can talk to your study doctor about any questions or concerns you have about this study. Contact
your study doctor __________________ [name(s)] at __________________ [telephone number].
For questions about your rights while taking part in this study, call the ________________________ [name
of center] Institutional Review Board (a group of people who review the research to protect your rights) at
__________________ (telephone number). [Note to Local Investigator: Contact information for patient
representatives or other individuals in a local institution who are not on the IRB or research team but take calls
regarding clinical trial questions can be listed here.]
*You may also call the Operations Office of the NCI Central Institutional Review Board (CIRB) at 888-6573711 (from the continental US only). [*Only applies to sites using the CIRB.]
Please note: This section of the informed consent form is about additional research that is being done
with people who are taking part in the main study. You may take part in this additional research if you
want to. You can still be a part of the main study even if you say ‘no’ to taking part in this additional
research.
You can say “yes” or “no” to each of the following studies. Below, please mark your choice for each
study.
(12/10/13) Note to Institutions: On March 22, 2012, the Quality of Life (QOL) Substudy of RTOG 0534
closed to patient enrollment, as the substudy met its patient enrollment goal. After closure to enrollment
of the QOL substudy, new patients will not be offered the opportunity to participate in the following part
of the RTOG 0534 study. Institutions should follow their local IRB policy regarding removal of the QOL
study text from the sample consent.
Quality of Life (QOL) Study
We want to know your view of how your life has been affected by cancer and its treatment. This “Quality of life”
study looks at how you are feeling physically and emotionally during your cancer treatment. It also looks at how
you are able to carry out your day-to-day activities and how your cancer and cancer treatment may affect your
thinking skills (neurocognitive part of QOL study).
This information will help doctors better understand how patients feel during treatments and what effects the
medicines are having. In the future, this information may help patients and doctors as they decide which
medicines to use to treat cancer.
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You will be asked to complete some questionnaires at the following time points:
 4 questionnaires immediately before you enroll in the study
 4 questionnaires during week 6 of radiation therapy
 4 questionnaires at year 1 and year 5
Neurocognitive Part of QOL Study
You will be asked to take part in a test of your thinking skills at the following time points:
 immediately before you enroll in the study
 during week 6 of radiation therapy
 at year 1 and year 5
It takes about 25 minutes to fill out the questionnaires and about 20 minutes to complete the test of thinking skills.
If any questions make you feel uncomfortable, you may skip those questions and not give an answer.
If you decide to take part in this study, the only things you will be asked to do is fill out the questionnaires and
take part in the test of thinking skills. You may change your mind about completing the questionnaires or the test
of thinking skills at any time, and you may chose to stop answering the questionnaires or taking part in the test of
thinking skills altogether at any time.
Just like in the main study, we will do our best to make sure that your personal information will be kept private.
Please circle your answer.
I choose to take part in the Quality of Life Study. I agree to fill out the Quality of Life questionnaires.
YES
NO
I choose to take part in the neurocognitive portion of the Quality of Life Study. I agree to take part in a test of
my thinking skills.
YES
NO
Use of Tissue, Blood, and Urine for Research
About Using Tissue, Blood, and Urine for Research (11/23/11)
You have had surgery to remove your prostate and your cancer. Your doctors have removed and examined some
of this tissue to look at the amount and grade of the cancer and to see if the cancer extended outside of the
prostate. The results of these tests will be given to you by your study doctor and will be used to plan your care.
We would like to keep some of the tissue that is left over from your surgery for future research. If you agree, this
tissue will be kept and may be used in research to learn more about cancer and other diseases. Please read the
information sheet called "How is Tissue Used for Research" to learn more about tissue research. This information
sheet is available to all at the following web site:
http://cdp.cancer.gov/humanSpecimens/ethical_collection/patient.htm
In addition, if you agree to participate in this part of the study, you will have blood drawn and urine collected
before you start radiation therapy, during the 6th week of radiation therapy, at 3, 6, and 12 months in year 1, then
yearly for 6 years after completion of treatment. We would like to keep about two tablespoons of blood and 5
tablespoons of urine at each of these times for future research. If you agree, this blood and urine will be kept to
be used in research to learn more about cancer and other diseases
Your tissue, blood, and urine may be helpful for research. The research that may be done is not designed
specifically to help you. It might help people who have cancer and other diseases in the future. Reports about
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research done with your tissue, blood and urine will not be given to you or your study doctor. These reports will
not be put in your health record. The research will not have an effect on your care.
Things to Think About
The choice to let us keep the left over tissue, blood, and urine for future research is up to you. No matter what you
decide to do, it will not affect your care or your participation in the main part of the study.
If you decide now that your tissue, blood, and urine can be kept for research, you can change your mind at any
time. Just contact us and let us know that you do not want us to use your tissue, blood, and urine. Then any
tissue, blood, or urine that remains will no longer be used for research and will be returned to the institution that
submitted it.
In the future, people who do research may need to know more about your health. While the study
doctor/institution may give them reports about your health, it will not give them your name, address, phone
number, or any other information that will let the researchers know who you are.
Sometimes tissue is used for genetic research (about diseases that are passed on in families). Even if your
tissue, blood, and urine are used for this kind of research, the results will not be put in your health records.
Your tissue, blood, and urine will be used only for research and will not be sold. The research done with your
tissue may help to develop new products in the future.
Benefits
The benefits of research using tissue include learning more about what causes cancer and other diseases, how
to prevent them, and how to treat them.
Risks
The greatest risk to you is the release of information from your health records. We will do our best to make sure that your
personal information will be kept private. The chance that this information will be given to someone else is very small.
Making Your Choice
Please read each sentence below and think about your choice. After reading each sentence, circle "Yes" or
"No". If you have any questions, please talk to your study doctor or nurse, or call our research review board at
IRB's phone number.
No matter what you decide to do, it will not affect your care.
1. My tissue, blood, and urine may be kept for use in research to learn about, prevent, or treat cancer.
Yes
No
2. My tissue, blood, and urine may be kept for use in research to learn about, prevent or treat other health
problems (for example: diabetes, Alzheimer's disease, or heart disease).
Yes
No
3. Someone may contact me in the future to ask me to take part in more research.
Yes
No
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Where can I get more information? (11/23/11)
You may call the National Cancer Institute's Cancer Information Service at:
1-800-4-CANCER (1-800-422-6237)
You may also visit the NCI Web site at http://cancer.gov/

For NCI’s clinical trials information, go to: http://cancer.gov/clinicaltrials/

For NCI’s general information about cancer, go to http://cancer.gov/cancerinfo/
You will get a copy of this form.
If you want more information about this study, ask your study doctor.
Signature
I have been given a copy of all _____ [insert total of number of pages] pages of this form. I have read it or it
has been read to me. I understand the information and have had my questions answered. I agree to take
part in this study.
Participant ________________________________
Date _____________________________________
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APPENDIX II: STUDY PARAMETER TABLE (See Sections 11.2 & 11.3 for details) [2/13/08] [1/8/09] [10/22/09] [3/24/10]
During Treatment
Follow up After RT
Assessment
Pretreatment
(May be required
for eligibility)
Arms 2 &
3: Within 2
wks prior
to start of
RT
Weekly
during
RT
During 6th
week of RT
1.5
Mo
3
Mo
6
Mo
9
Mo
12
Mo
q 3 mos.
for 1 yr.
q 6 mos.
for 6 yrs.
q 6 mo
thereafter
Prostate biopsy with
Prostatectomy
Gleason score
Gleason
History/physical
X
X
X
X
X
X
Performance status
X
X
X
X
X
X
CT or MRI of pelvis*
X
Bone Scan*
X
Digital rectal exam
X
X
X
X
X
CBC w/ diff
X
X
X
X
X
AST or ALT
X
X
X
X*
X* X
PSA *
X
X
X
X** X** X** X**
X**
X**
Testosterone
X
X
X
X
X
X
X
X
X
X
Alk phos
Recommended
CT-sim
X
Urethrogram or MRIRecommended
sim
Tissue for central
Required
review
Tissue for banking
If patient consents
Blood†, urine for
If patient consents
X
X
X
X
banking
AUA SI
X
X
X
X
X
X
X
EPIC, HSCL-25, EQIf patient consents
X
X
5D,
Document use of
sexual meds/devices
HVLT-R, Trail making
If patient consents
X
X
A & B, COWAT
Adverse event eval*
X
X
X
X
X
*And as needed based on reporting requirements.
** If the PSA is ≤ 0.1 ng/mL, PSA will be drawn every 3 months from the completion of radiotherapy for two years, and at 6-month intervals thereafter.
If PSA post-radiotherapy is ≥ 0.2 ng/mL, then continue at 3-month intervals (See Section 11.3.2.3).
† Includes blood for beta-amyloid testing.
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Annually
thereafter
X
X
Long-term
Follow up
As indicated
in Sections
11.2 and
11.3
X
X
X
X
X
X
For 6 yrs
X
Year 5
Year 5
X
X
APPENDIX III (10/22/09)
ZUBROD PERFORMANCE SCALE
0
Fully active, able to carry on all predisease activities without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry
work of a light or sedentary nature. For example, light housework, office
work
2
Ambulatory and capable of all self-care but unable to carry out any work
activities. Up and about more than 50% of waking hours
3
Capable of only limited self-care, confined to bed or chair 50% or more of
waking hours
4
Completely disabled. Cannot carry on self-care. Totally confined to bed
5
Death
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APPENDIX IV
AJCC STAGING SYSTEM
PROSTATE, 6th Edition
DEFINITION OF TNM
Primary Tumor, Clinical (T)
TX
Primary tumor cannot be assessed
T0
No evidence of primary tumor
T1
Clinically inapparent tumor neither palpable nor visible by imaging
T1a
Tumor incidental histologic finding in 5% or less of tissue resected
T1b
Tumor incidental histologic finding in more than 5% of tissue resected
T1c
Tumor identified by needle biopsy (e.g., because of elevated PSA)
T2
Tumor confined with prostate*
T2a
Tumor involves one-half of one lobe or less
T2b
Tumor involves more than one-half of one lobe but not both lobes
T2c
Tumor involves both lobes
T3
Tumor extends through prostate capsule**
T3a
Extracapsular extension (unilateral or bilateral)
T3b
Tumor involves the seminal vesicle(s)
T4
Tumor is fixed or invades adjacent structures other than seminal vesicles: bladder neck, external
sphincter, rectum, levator muscles and/or pelvic wall
*Note: Tumor found in one or both lobes by needle biopsy, but not palpable or reliably visible by imaging, is
classified as T1c.
**Note: Invasion into the prostatic apex or into (but not beyond) the prostatic capsule is not classified as T3, but
as T2.
Regional Lymph Nodes (N) (1/8/09)
Clinical
NX
Regional lymph nodes cannot be assessed
N0
No regional lymph node metastasis
N1
Metastasis in regional lymph node(s)
Pathologic
pNX
Regional nodes not sampled
pN0
No positive regional nodes
pN1
Metastases in regional node(s)
Primary Tumor, Pathologic (pT)
pT2* Organ confined
pT2a Unilateral, involving one-half of one lobe or less
pT2b Unilateral, involving more than one-half of one lobe but not both lobes
pT2c Bilateral disease
pT3
Extraprostatic extension
pT3a Extraprostatic extension**
pT3b Seminal vesicle invasion
pT4
Invasion of bladder, rectum
*Note: There is no pathologic T1 classification.
**Note: Positive surgical margin should be indicated by an R1 descriptor (residual microscopic disease).
***Note: The type of prostatectomy (radical retropubic, perineal, robotic) should be recorded.
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APPENDIX IV (Continued)
AJCC STAGING SYSTEM
PROSTATE, 6th Edition
Distant Metastasis (M)*
MX
Presence of distant metastasis cannot be assessed (not evaluated by any modality)
M0
No distant metastasis
M1
Distant metastasis
M1a
Nonregional lymph node(s)
M1b
Bone(s)
M1c
Other site(s) with or without bone disease
*Note:
When more than one site of metastasis is present, the most advanced category is used;
pM1c is most advanced.
Histopathologic Grade (G)
GX
Grade cannot be assessed
G1
Well-differentiated (slight anaplasia [Gleason 2-4])
G2
Moderately differentiated (moderate anaplasia [Gleason 5-6])
G3-4
Poorly undifferentiated or undifferentiated (marked anaplasia [Gleason 7-10])
Stage Grouping
Stage I
T1a
N0
M0
G1
Stage II
T1a
T1b
T1c
T1
T2
N0
N0
N0
N0
N0
M0
M0
M0
N0
M0
G2, G3-4
Any G
Any G
Any G
Any G
Stage III
T3
N0
M0
Any G
Stage IV
T4
Any T
Any T
N0
N1
Any N
M0
M0
M1
Any G
Any G
Any G
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APPENDIX V (12/10/13)
APPENDICES FOR RTOG BIOSPECIMEN COLLECTION
RTOG Blood Collection Kit Instructions
RTOG Urine Collection Kit Instructions
Shipping Instructions:
U.S. Postal Service Mailing Address: For FFPE or Non-frozen Specimens Only
Campus Box 1800
San Francisco, CA 94143-1800
Courier Address (FedEx, UPS, etc.): For Frozen or Trackable Specimens



Include all RTOG paperwork in pocket of biohazard bag.
Check that the Specimen Transmittal Form (STF) has the consent boxes checked off.
Check that all samples are labeled with the RTOG study and case number, and include date of collection
as well as collection time point (e.g., pretreatment, post-treatment).

FFPE Specimens:
o Slides should be shipped in a plastic slide holder/slide box. Place a small wad of padding in top of the
container. If you can hear the slides shaking it is likely that they will break during shipping.
o FFPE Blocks can be wrapped with paper towel, or placed in a cardboard box with padding. Do not wrap
blocks with bubble wrap. Place padding in top of container so that if you shake the container the blocks
are not shaking. If you can hear the slides shaking it is likely that they will break during shipping.
o Slides, Blocks, or Plugs can be shipped ambient or with a cold pack either by United States Postal
Service (USPS) to the USPS address (94143) or by Courier to the Street Address (94115). Do NOT
ship on Dry Ice.

Frozen Specimens:
o Multiple cases may be shipped in the same cooler, but make sure each one is in a separate bag and
clearly identified.
o Place specimens and absorbent shipping material in Styrofoam cooler filled with dry ice (at least 7 lbs).
There should be plenty of dry ice under and above the specimens. If the volume of specimens is
greater than the volume of dry ice then ship in a larger Styrofoam box, or two separate boxes. Any
Styrofoam box can be used, as long as it is big enough.
o Specimens received thawed due to insufficient dry ice or shipping delays will be discarded and the site
will be notified.
o Send frozen specimens via overnight courier to the address above. Specimens should only be shipped
Monday through Wednesday (Monday-Tuesday for Canada) to prevent thawing due to delivery delays.
Saturday or holiday deliveries cannot be accepted. Samples can be stored frozen at -80 C until ready
to ship.

For Questions regarding collection/shipping please contact the RTOG Biospecimen Resource by
e-mail: [email protected] or phone: 415-476-RTOG (7864) or Fax: 415-476-5271.
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APPENDIX V
BLOOD COLLECTION KIT AND INSTRUCTIONS
This Kit is for collection, processing, storage, and shipping of serum, plasma, or whole blood (as
specified by the protocol):
Kit contents:
 One Red Top tube for serum (A)
 One Purple Top EDTA tube for plasma (B)
 One Purple Top EDTA tube for Whole Blood (C)
 Twenty-five (25) 1 ml cryovials
 Biohazard bags (3) and Absorbent shipping material (3)
 Styrofoam container (inner) and Cardboard shipping (outer) box
 UN1845 DRY Ice Sticker and UN3373 Biological Substance Category B Stickers
 Specimen Transmittal Form (STF) and Kit Instructions
PREPARATION AND PROCESSING OF SERUM, PLASMA AND WHOLE BLOOD:
(A) Serum (if requested): Red Top Tube
 Label as many 1ml cryovials (5 to 10) as necessary for the serum collected. Label them with the
RTOG study and case number, collection date, time, and time point, and clearly mark cryovials
“serum”.
Process:
1. Allow one red top tube to clot for 30 minutes at room temperature.
2. Spin in a standard clinical centrifuge at ~2500 RPM for 10 minutes at 4C (preferred). If sites are
unable to process samples at 4C then spinning at room temperature is acceptable if done within 2
hours of draw but must be noted on the STF.
3. Aliquot 0.5 ml serum into as many cryovials as are necessary for the serum collected (5 to 10)
labeled with RTOG study and case numbers, collection date/time, protocol time-point collected (e.g.
pretreatment, post-treatment), and clearly mark specimen as “serum”.
4. Place cryovials into biohazard bag and immediately freeze at -70 to -90 C, and store frozen until
ready to ship. See below for storage conditions.
5. Store serum at -70 to -90 C until ready to ship on dry ice. See below for storage conditions.
PLEASE MAKE SURE THAT EVERY SPECIMEN IS LABELED and include collection time point on the STF.
(B) Plasma (If requested): Purple Top EDTA tube #1
 Label as many 1ml cryovials (5 to 10) as necessary for the plasma collected. Label them with the
RTOG study and case number, collection date, time, and time point, and clearly mark cryovials
“plasma”.
Process:
1. After collection, invert tube(s) multiple times to ensure adequate mixing of EDTA.
2. Centrifuge specimen(s) within one hour of collection in a standard clinical centrifuge at ~2500 RPM
for 10 minutes at 4C (preferred). If sites are unable to process samples at 4C then spinning at room
temperature is acceptable if done within 2 hours of draw but must be noted on the STF..
3. If the interval between specimen collection and processing is anticipated to be more than one hour,
keep specimen on ice until centrifuging is performed.
4. Carefully pipette and aliquot 0.5 ml plasma into as many cryovials as are necessary for the plasma
collected (5 to 10) labeled with RTOG study and case numbers, collection date/time, time point
collected and clearly mark specimen as “plasma”. Avoid pipetting up the buffy coat layer.
5. Place cryovials into biohazard bag and immediately freeze at -70 to -90C.
6. Store frozen plasma until ready to ship on dry ice.
7. See below for storage conditions.
PLEASE MAKE SURE THAT EVERY SPECIMEN IS LABELED and include collection time point on the STF.
(continued on next page)
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APPENDIX V
RTOG BLOOD COLLECTION KIT INSTRUCTIONS (continued)
(C) Whole Blood for DNA (if requested): Purple Top EDTA tube #2
 Label as many 1ml cryovials (3 to 5) as necessary for the whole blood collected..Label them with the
RTOG study and case number, collection date/time, and time point, and clearly mark cryovials “blood”.
Process:
1. After collection, invert tube(s) multiple times to ensure adequate mixing of EDTA. Blood can also be
mixed for 5 minutes on a mixer at room temperature.
2. Carefully pipette and aliquot 1.0 ml blood into as many cryovials as are necessary for the blood
collected (3 to 5) labeled with RTOG study and case numbers, collection date/time, time point
collected and clearly mark specimen as “blood”.
3. Place cryovials into biohazard bag and freeze immediately at -70 to -80 Celsius.
4. Store blood samples frozen until ready to ship on dry ice.
5. See below for storage conditions.
PLEASE MAKE SURE THAT EVERY SPECIMEN IS LABELED and include collection time point on STF.
Freezing and Storage:
 Freeze Blood samples in a -80C Freezer or on Dry Ice or snap freeze in liquid nitrogen.
 Store at –80C (-70C to -90C) until ready to ship.
If a -80C Freezer is not available,
 Samples can be stored short term in a -20C freezer (non-frost free preferred) for up to
one week (please ship out Monday-Wednesday only; Canada: Monday-Tuesday only).
OR:
 Samples can be stored in plenty of dry ice for up to one week, replenishing daily (please
ship out on Monday-Wednesday only; Canada: Monday-Tuesday only).
OR:
 Samples can be stored in liquid nitrogen vapor phase (ship out Monday-Wednesday
only; Canada: Monday-Tuesday only).
 Please indicate on Specimen Transmittal Form the storage conditions used and time stored.
Shipping/Mailing:
 Ship specimens on Dry Ice overnight Monday-Wednesday (Monday-Tuesday from Canada) to prevent
thawing due to delivery delays. Saturday and holiday deliveries cannot be accepted.
 Include all RTOG paperwork in a sealed plastic bag and tape to the outside top of the Styrofoam box.
 Wrap frozen specimens of same type (i.e., all serum together, plasma together and whole bloods
together) in absorbent shipping material and place each specimen type in a separate biohazard bag.
Place specimen bags into the Styrofoam cooler and fill with plenty of dry ice (7-10 lbs/3.5kg minimum).
Add padding to avoid the dry ice from breaking the tubes.
 Place Styrofoam coolers into outer cardboard box, and attach shipping label and UN3373 and UN1895
stickers to outer cardboard box.
(continued on next page)
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APPENDIX V
RTOG BLOOD COLLECTION KIT INSTRUCTIONS (continued)


Multiple cases may be shipped in the same cooler, but make sure each one is in a separate bag and that
there is enough room for plenty of dry ice. Add padding to avoid the dry ice from breaking the tubes.
For questions regarding collection, shipping or to order a Blood Collection Kit, please e-mail
[email protected] or call (415)476-7864.
Shipping Address:
Courier Address (FedEx, UPS, etc.): For all Frozen Specimens
For questions, call 415-476-RTOG (7864) or e-mail: [email protected]
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RTOG 0534
APPENDIX V
RTOG URINE COLLECTION KIT INSTRUCTIONS (continued)
This Kit is for collection, processing, storage, and shipping of urine specimens.
Kit Contents:



 Two 15 ml polypropylene centrifuge tubes
 Biohazard bags
 Parafilm for sealing outside of tubes
One (1) Sterile Urine collection cup
Two 7 ml disposable pipettes
Absorbent paper towel
Preparation and Processing of Urine Specimens:
Process:

A clean catch urine specimen will be collected. To collect the specimen, use the following instructions:
o Males should wipe clean the head of the penis and females need to wipe between the labia with soapy
water/cleansing wipes to remove any contaminants.
o After urinating a small amount into the toilet bowl to clear the urethra of contaminants, collect a sample of
urine in the collection cup.
o After 10-25 mL urine has been collected, remove the container from the urine stream without stopping the
flow of urine.
o Finish voiding the bladder into the toilet bowl.

Aliquot 5-10 mls of Urine into each of two 15 ml polypropylene centrifuge tubes (disposable pipets are provided in
the kit). Do not fill with more than 10 mls to avoid cracking of tubes due to expansion during freezing. Replace the
cap and tighten on the tubes. Make sure the cap is not cross-threaded or placed on incorrectly or leaking will
occur.

Use parafilm to seal the cap around the outside rim of the urine tube to prevent leakage.

Discard remaining Urine and collection cup.

Label the specimen with the RTOG study and case number, collection date and time, time point of collection, and
clearly mark specimens as “urine”.

Wrap Urine Tubes with absorbent material (paper towels) and place into biohazard bag and seal the bag. Freeze
and store Urine samples in a -20C or -80C freezer until ready to ship.
PLEASE MAKE SURE THAT EVERY SPECIMEN IS LABELED with RTOG study and case numbers,
collection date/time, and time point collected (e.g. pretreatment, post-treatment).
Storage and Shipping:
Freezing and Storage:

Urine specimens may be sent in batches or with other frozen biospecimens, if within 30-60 days of collection. Store at
-20C or -80C (-70C to -90C) until ready to ship. If a -80C Freezer is not available:

Samples can be stored short term in a -20 C freezer (non-frost free preferred) for up to one week (please
ship out Monday-Wednesday only; Canada: Monday-Tuesday only).
OR:

Samples can be stored in plenty of Dry Ice for up to one week, replenishing daily (please ship out MondayWednesday only; Canada: Monday-Tuesday only).

Please indicate on Specimen Transmittal Form the storage conditions used and time stored.
Shipping/Mailing:







Ship specimens on Dry Ice overnight Monday-Wednesday (Monday-Tuesday from Canada) to prevent thawing
due to delivery delays. Saturday and holiday deliveries cannot be accepted.
Include all RTOG paperwork in a sealed plastic bag and tape to the outside top of the Styrofoam box.
Place sealed specimen bags into the Styrofoam cooler and fill with plenty of dry ice (7-10 lbs/3.5kg minimum). Add
padding to avoid the dry ice from breaking the tubes.
Place Styrofoam coolers into outer cardboard box, and attach shipping label and UN3373 and UN1895 stickers to
outer cardboard box.
Multiple cases may be shipped in the same cooler, but make sure each one is in a separate bag and that there is
enough room for plenty of dry ice. Add padding to avoid the dry ice from breaking the tubes.
Samples received thawed will be discarded, and a notification will be sent immediately to the Principal Investigator
and Clinical Research Assistant of the submitting institution. The institution should send a subsequent sample,
collected as close as possible to the original planned collection date.
For questions regarding ordering, collection, or shipping of a Urine Collection Kit, please e-mail
[email protected] or call (415)476-7864 or fax (415) 476-5271.
Shipping Address: FedEx/UPS/Courier address (For all frozen samples)
RTOG Biospecimen Resource at UCSF
2340 Sutter Street, Room S341, San Francisco, CA 94115
Contact Phone: (415) 476-RTOG(7864)
76
RTOG 0534
APPENDIX VI (12/10/13)
RTOG 0534 Neurocognitive Battery: Certification Process and Test Instructions
Examiner Certification
Prior to testing a patient, potential examiners must view the training video and take the post-test. Administrators
that have previously been certified for RTOG 0525, 0614, or 0825 do not need to go through the training
procedure again, but must fax the certification worksheet to Dr. Wefel, and indicate that they have previously
been certified. Please note previous certification for RTOG 0212, 0214 and 0424 is not sufficient. Training, which
takes 15-30 minutes, will involve review of the forms and instructions for the administration and scoring of the
neurocognitive test battery (Hopkins Verbal Learning Test - Revised, Trail Making Test Parts A and B, and
Controlled Oral Word Association Test) and discussion of study-specific logistics.
The trainee will then complete a practice assessment for review. This assessment must be faxed to Dr. Wefel
(see certification worksheet below), and he will review the results with the trainee. If the trainee demonstrates
competency, he/she will be approved to administer the tests to study subjects as part of RTOG 0534. Dr. Wefel
will fax his approval to the CTSU for documentation and to ensure that only certified examiners are testing
subjects on RTOG 0534.
Examiner Certification Worksheet
This worksheet must be completed and signed by the person requesting certification and submitted to Dr. Wefel
prior to the registration of patients to RTOG 0534.
(Y)
1. Have you reviewed the Neuropsychological Test Instructions in Appendix VI of the 0534
protocol?
(Y)
2. Have you been trained by Dr. Wefel at an RTOG meeting or by teleconference, watched the
0534 Neuropsychological Test Administration video, or previously been certified for RTOG 0525,
0614, or 0825 within the past 6 months?
(Y)
3. Have you completed and submitted the post-test associated with the training video and a
“practice” neuropsychological assessment?
(Y)
4. Have you contacted Dr. Wefel (See Section 11.9) for test translations and found that
no translations are available for your institution?
Signature of test administrator
Date
(Person who read Appendix VI, completed a RTOG meeting training or teleconference or watched video and
completed the “practice” Neuropsychological Assessment)
Printed name of test administrator
___
Institution number/Name-NCI Code
Telephone number of test administrator
___
Fax number of test administrator
If you have any questions regarding the certification, please contact Dr. Wefel. Once you have completed this
form, please attach the Neuropsychological Assessment forms from the “practice” individual and the training
video post test and and fax to:
Dr. Jeffrey S. Wefel; phone: 713.563.0514; FAX: 713.794.4999; e-mail: [email protected]
For Dr. Wefel’s Use Only (To fax to 215-569-0206, CTSU)
(Y/N)
The above individual has been certified for administering the neurocognitive assessments for this
study.
Signature
Date
77
RTOG 0534
APPENDIX VI (Continued)
Testing: General Information
1. As noted above, copies of the test forms and summary sheets for the first case from each site must be
faxed to Dr. Wefel for review.
2. Testing should be completed in one session. Test instructions must be followed verbatim with every
patient at every assessment visit.
3. Tests should be administered in the following order to every patient and at each assessment visit: HVLTR Part A (Learning Trials); Trail Making Test Part A; Trail Making Test Part B; COWAT; HVLT-R Part B
(Delayed Recall); and the HVLT-R Part C (Delayed Recognition).
4. Follow the instructions on the Forms Packet Index before submitting forms to RTOG.
5. All test results are recorded on the Neurocognitive Evaluation Summary Form (CS), which is found in the
Forms Packet. Study/case-specific labels must be applied to all forms.
6. Note: Test results are not submitted to Dr. Wefel, nor to RTOG Headquarters (test results are recorded
on forms and submitted). Sites should keep all original test records, and test results must remain on file
at the institution as source documentation pending request for submission by RTOG or a Study Chair. In
the event of questions, contact Dr. Wefel.
7. Patients should not be given copies of their tests to avoid learning the material between test
administrations.
8. The HVLT-R and the COWAT have alternate forms or versions in order to reduce the effects of practice.
See the test instructions below for the versions to be administered at pre-treatment and subsequent
sessions. The forms should continue to be alternated in this order for the duration of the study. The
forms packet will contain alternate versions of these neuropsychological tests.
Before dismissing the patient, thank him/her for their cooperation. Remind the patient of their next
appointment and that these tests will be repeated.
In the event that a patient cannot complete a given test, please write the reason(s) on the test form AND the
data summary form.
Testing: Specific Instructions
Note: Administer the tests in the following order to every patient at each assessment visit.
1. HOPKINS VERBAL LEARNING TEST - REVISED (HVLT-R)
This test has three parts and six alternate forms (only the first 4 forms will be used in this study):
Part A - Free Recall: Complete the three learning trials first
Part B - Delayed Recall: Complete after Trail Making Tests and COWAT
Part C - Delayed Recognition: Complete after Delayed Recall
Part A – Free Recall: Trial 1
Examiner: “I am going to read a list of words to you. Listen carefully, because when I am through, I’d like
you to tell me as many of the words as you can remember. You can tell them to me in any order. Are you
ready?”

Read the words at the rate of one word every 2 seconds.
Examiner: “OK. Now tell me as many of those words as you can remember.”

Check off the words the patient recalls on the form.

If a word is said that is not in the list (for example, “intrusion”), do not write that word on the form and say
nothing to the patient about the word not being on the list.

If the patient does not produce any words for 10-15 seconds, ask the patient if he/she can remember any
more words.

If not, move on to trial 2. Later, you can record the number of words that were correctly repeated on the
summary form.
Examiner: “Now we are going to try it again. I am going to read the same list of words to you. Listen
carefully, and tell me as many of the words as you can remember, in any order, including the words you
told me the first time.”


78
RTOG 0534



more words.
If not, move on to trial 3. Later, you can record the number of words that were correctly repeated on the
summary form.
Examiner: “I am going to read the list one more time. As before, I’d like you to tell me as many of the
words as you can remember, in any order, including all the words you’ve already told me.”




more words.

Do not tell the respondent that recall of the words will be tested later.

Record the time on the clock that you complete ‘Part A – Free Recall’ (for example, 1:00 p.m.) on the
designated space on the HVLT-R form.
2. TRAIL MAKING TEST [Timed Test]
Part A – Sample: Place the Sample A worksheet flat on the table, directly in front of the patient (the bottom of
the worksheet should be approximately six inches from the edge of the table). Give the patient a black pen and
say:
Examiner: “On this page (point) are some numbers. Begin at number 1 (point to 1) and draw a line from 1
to 2 (point to 2), 2 to 3 (point to 3), 3 to 4 (point to 4), and so on, in order, until you reach the end (point to
the circle marked END). Draw the lines as fast as you can. Ready, begin.”
If the patient completes Sample A correctly, and in a manner demonstrating that s/he understands what to do,
proceed immediately to Test A. If the patient makes a mistake on Sample A, point out the error and explain it.
The following explanations of mistakes serve as illustrations:
 This is where you start (point to number 1).
 You skipped this circle (point to the circle omitted).
 You should go from number 1 to 2, 2 to 3, and so on, until you reach the circle marked END.
If it is clear that the patient intended to touch a circle but missed it, do not count it as an omission. Remind the
patient, however, to be sure to touch the circles. If the patient still cannot complete Sample A, take his/her hand
and guide him/her through the trail using the opposite end of the pen, lightly touching the worksheet to avoid
making marks on he copy. Then say:
Examiner: “Remember, begin at number 1 (point to 1) and draw a line from 1 to 2 (point to 2), 2 to 3 (point
to 3), 3 to 4 (point to 4) and so on, in order, until you reach the circle marked END (point). Do not skip
around, but go from one number to the next in proper order. Remember to work as fast as you can.
Ready, begin.”
If the patient does not succeed, or it becomes evident that s/he cannot do the task, DISCONTINUE testing and
indicate the corresponding reason on the Trail Making Data Sheet. If the patient completes Sample A correctly
and appears to understand what to do, proceed immediately to Part A.
Part A – Test: After the patient has completed Sample A, place the Part A test worksheet directly in front of the
patient and say:
Examiner: “Good! Let’s try the next one. On this page are numbers from 1 to 25. Do this the same way.
Begin at number 1 (point) and draw a line from 1 to 2 (point to 2), 2 to 3 (point to 3), 3 to 4 (point to 4) and
so on, in order, until you reach the circle marked END (point). Do not skip around, but go from one
number to the next in proper order. Remember to work as fast as you can. Ready, begin.”
 Start timing as soon as the instruction is given to “begin”
79
RTOG 0534





Watch closely in order to catch any errors as soon as they are made. If the patient makes an error, call it
to his/her attention immediately and have him/her proceed from the point the mistake occurred
The patient must complete the test in 3 minutes or less.
DO NOT STOP TIMING UNTIL HE/SHE REACHES THE CIRCLE MARKED “END”.
Collect the worksheet and record the time to completion on the Trail Making Data Sheet in minutes and
seconds
If the patient does not complete the test within 3 minutes terminate the testing. The test can also be
discontinued if the patient is extremely confused and is unable to perform the task. Collect the
worksheet and complete the Trail Making Data Sheet indicating the reason the test was terminated and
the last correct number reached on the test.
Part B – Sample: Place the Sample B worksheet flat on the table, directly in front of the patient (the bottom of
the worksheet should be approximately six inches from the edge of the table) and say:
Examiner: “On this page (point) are some numbers and letters. Begin at number 1 (point to 1) and draw a
line from 1 to A (point), A to 2 (point to 2), 2 to B (point to B), B to 3 (point to 3), 3 to C (point to C) and so
on, in order, until you reach the end (point to the circle marked END). Remember, first you have a number
(point to 1), then a letter (point to A), then a number (point to 2), then a letter (point to B), and so on. Draw
the lines as fast as you can. Ready, begin.”
If the patient completes Sample B correctly, and in a manner demonstrating that s/he understands what to do,
proceed immediately to Part B. If the patient makes a mistake on Sample B, point out the error and explain it.
The following explanations of mistakes serve as illustrations:
 You started with the wrong circle. This is where you start (point to number 1)
 You skipped this circle (point to the circle omitted)
 You should go from number 1 (point) to A (point), A to 2 (point to 2), 2 to B (point to B), B to 3
(point to 3) and so on, until you reach the circle marked END (point).
If it is clear the patient intended to touch a circle but missed it, do not count it as an omission. Remind the patient,
however, to be sure to touch the circles. If the patient still cannot complete Sample B, take their hand and guide
them through the trail using the opposite end of the pen, lightly touching the worksheet to avoid making marks on
the copy. Then say:
Examiner: “Now you try it. Remember, begin at number 1 (point to 1) and draw a line from 1 to A (point to
A), A to 2 (point to 2), 2 to B (point to B), B to 3 (point to 3) and so on, in order, until you reach the circle
marked END (point). Ready, begin.”
If the patient does not succeed or it becomes evident that s/he cannot do the task, DISCONTINUE testing and
indicate the corresponding reason on the Trail Making Data Sheet. If the patient completes Sample A correctly
and appears to understand what to do, proceed immediately to Part A.
Part B – Test:
After the patient has completed Sample B, place the Part B Worksheet directly in front of the patient and say:
Examiner: “Good! Let’s try the next one. On this page are both numbers and letters. Do this the same
way. Begin at number 1 (point) and draw a line from 1 to A (point to A), A to 2 (point to 2), 2 to B (point to
B), B to 3 (point to 3), 3 to C (point to C) and so on, in order, until you reach the circle marked END (point).
Remember, first you have a number (point to 1), then a letter (point to A), then a number (point to 2), then
a letter (point to B), and so on. Do not skip around, but go from one circle to the next in the proper order.
Draw the lines as fast as you can. Ready, begin.”
 Start timing as soon as the instruction is given to “begin”.
 Watch closely in order to catch any errors as soon as they are made. If the patient makes an error, call it
to his/her attention immediately and have him/her proceed from the point the mistake occurred
 The patient must complete the test in 5 minutes or less.
 DO NOT STOP TIMING UNTIL HE/SHE REACHES THE CIRCLE MARKED “END”.
 Collect the worksheet and record the time to completion on the Trail Making Data Sheet in minutes and
seconds.
80
RTOG 0534

If the patient does not complete the test within 5 minutes terminate the testing. The test can also be
discontinued if the patient is extremely confused and is unable to perform the task. Collect the
worksheet and complete the Trail Making Data Sheet indicating the reason the test was terminated and
the last correct number or letter reached on the test.
3. CONTROLLED ORAL WORD ASSOCIATION TEST (COWAT) [Timed Test]
This test has three parts (letters) and two alternate forms.
Examiner: “I am going to say a letter of the alphabet, and I want you to say as quickly as you can all of
the words that you can think of that begin with that letter. You may say any words at all, except proper
names such as the names of people or places. So you would not say ‘Rochester’ or ‘Robert’. Also, do
not use the same word again with a different ending, such as ‘Eat,’ ‘Eats,’ and ‘Eating.’
“For example, if I say ‘s,’ you could say ‘sit,’ ‘shoe,’ or ‘show.’ Can you think of other words beginning
with the letter ‘s’?”
Wait for the patient to give a word. If it is a correct response, say “good”, and ask for another word beginning
with the letter “s”. If a second appropriate word is given, proceed to the test itself.
If the patient gives an inappropriate word on either occasion, correct the patient, and repeat the
instructions. If the patient then succeeds, proceed to the test.
If the patient fails to respond, repeat the instructions. If it becomes clear that the patient does not understand the
instructions or cannot associate, stop the procedure, and indicate the reason(s) on the scoring sheet.
If the patient has succeeded in giving two appropriate words beginning with the demonstration letter, say:
Examiner: “That is fine. Now I am going to give you another letter. Again, say all of the words beginning
with that letter that you can think of. Remember, no names of people or places, just ordinary words.
Also, if you should draw a blank, I want you to keep on trying until the time limit is up and I say STOP.”
“You will have a minute for each letter. The first letter is ‘___’” (see scoring sheet).
**Allow exactly one minute for each letter.**




If the patient discontinues before the end of the time period, encourage him/her to try to think of more
words.
If he/she is silent for 15 seconds, repeat the basic instruction and the letter (e.g., “Tell me all the words
you can think of that begin with a “c”).
No extension on the time limit is made in the event that instructions are repeated.
Continue the evaluation with the remaining two letters, allowing one minute for each.
Recording and Scoring:
 The record sheet provides lines on which the patient’s responses can be entered (e.g., write in the word
that is said by the patient). If his/her speed of word production is too fast to permit verbatim recording, a
“+” should be entered to indicate a correct response.

Incorrect responses either should not be recorded or, if recorded, should be struck through with a line.
 If the patient provides more responses than there are lines on the record sheet, keep writing the
responses (or a “+”) elsewhere on the record sheet.
 Count all the correct responses. The number of correct words should be indicated below each column
on the recording sheet and on the summary data form that is sent to the RTOG.
Comments on scoring:
 Note: It can be helpful for the first several patients and for patients known to be fast with their word
production to tape record the session for transcription at a later time.
81
RTOG 0534






The instructions include a specific prohibition against giving proper names or different forms of the same
word. Therefore, inflections of the same word (e.g., eat-eating; mouse-mice; loose-loosely; ran-run-runs)
are not considered correct responses.
Patients often give both a verb and a word derived from the verb or adjective (e.g., fun-funny; sadsadness). These are not considered correct responses. On the other hand, if the word refers to a
specific object (e.g., foot-footstool; hang-hanger), it would be counted as a correct answer.
Many words have two or more meanings (e.g., foot; can; catch; hand). A repetition of the word is
acceptable IF the patient definitely indicates the alternative meaning to you.
Slang terms are OK if they are in general use.
Foreign words (for example, pasta; passé; lasagna) can be counted as correct if they can be considered
part of English vocabulary (for example, in general use or found in the dictionary).
If the test is discontinued or omitted, please mark this on the bottom of the test form and indicate the
reason on the Tests Discontinued/Not Done CRF
4. HOPKINS VERBAL LEARNING TEST - REVISED (HVLT-R)
Part B – Delayed Recall

DO NOT READ THE WORD LIST AGAIN.

Record the time on the clock that you start ‘Part B – Delayed Recall’ (for example, 1:20 p.m.) on the
designated space on the HVLT-R form.

Administer ‘Part B – Delayed Recall’ after completing all Trail Making Tests and the COWAT. There
should be at least 15 minutes between ‘Part A’ and ‘Part B’. If the time is too short, allow the patients to
complete a questionnaire.
Examiner: “Do you remember that list of words you tried to learn before? Tell me as many of those
words as you can remember.”

Check the box on the corresponding line of the HVLT-R worksheet for each word the patient accurately
recalls.


more words.

If not, record the number of words that were correctly recalled on the summary form.
Part C – Delayed Recognition
Examiner: “Now I’m going to read a longer list of words to you. Some of them are words from the original
list, and some are not. After I read each word, I’d like you to say “Yes” if it was on the original list or “No”
if it was not. Was [word] on the list?”

Check either the “Y” (Yes) or “N” (No) box next to each word to indicate the patient’s response.

Guessing is allowed.

If the test is discontinued or omitted, please mark this on the bottom of the test form and indicate the
reason on the Tests Discontinued/Not Done CRF.
The score for this portion of the HVLT-R is the number of list words (i.e., words that in CAPS) correctly identified
(“yes” response) minus the number of non-list words (i.e., words in lower case) incorrectly identified (“yes”
response). Therefore, the actual score can range from –12 (no list words identified and all non-list words
identified) to +12 (all list words identified and no non-list words identified).
82
RTOG 0534

RADIATION THERAPY ONCOLOGY GROUP RTOG

Transcription

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